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Review

The Immune Regulatory Functions of CD226 and Its Implications in Immune-Mediated Diseases

by
Keyan Liu
1,†,
Yuanzhen Liu
2,†,
Huabao Xiong
2,* and
Zhaochen Ning
2,*
1
Department of Public Health, Jining Medical University, Jining 272067, China
2
Jining Key Laboratory of Immunology, Jining Medical University, Jining 272067, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomolecules 2025, 15(7), 1007; https://doi.org/10.3390/biom15071007
Submission received: 24 June 2025 / Revised: 8 July 2025 / Accepted: 10 July 2025 / Published: 14 July 2025
(This article belongs to the Section Molecular Medicine)
Browse Figure
Versions Notes

Abstract

CD226, a member of the immunoglobulin superfamily, serves as a critical regulator in various immunological processes. CD226 is expressed across immune and non-immune cells, with predominant expression being observed in natural killer (NK) cells and T cells. By engaging ligands CD155 and CD112, it orchestrates diverse signaling pathways that modulate T cell differentiation and effector functions while enhancing NK cell activation and cytotoxicity. Genetic polymorphisms and the dysregulated expression of CD226 are closely associated with susceptibility to autoimmune diseases, infectious diseases, allergic diseases, and cancer progression. Growing evidence highlight CD226’s emerging promise as a therapeutic target for immune-mediated diseases. The present work aims to review the current understanding of CD226’s role in immune responses and to comprehensively outline its multifaceted involvement in different immunological diseases, providing insights for future research to advance our mechanistic understanding of its roles in disease pathogenesis.

1. Introduction

CD226 is encoded by a conserved gene located on chromosome 18 in humans [1]. The protein comprises a leader sequence, two extracellular V-set Ig-like domains (D1 and D2), a transmembrane domain, and a cytoplasmic tail [2,3,4]. The binding interactions between CD226 and its ligands are predominantly governed by a conserved “lock-and-key” motif located within the D1 domain [5]. The cytoplasmic domain contains evolutionarily conserved tyrosine (Y322) and serine (S329) residues in humans (S326 and Y319 in mice), which undergo phosphorylation upon ligand engagement to initiate downstream signaling. CD226 exhibits broad expression across immune and non-immune cells. In humans and mice, its expression is detected on NK cells, T cells, natural killer T (NKT) cells, dendritic cells, B cells, endothelial cells, monocytes/macrophages, mast cells, hematopoietic precursor cells, and megakaryocyte/platelet lineages [6,7].
CD226 binds to CD155 (PVR) and CD112 (nectin-2), members of the nectin/nectin-like family. CD155 exhibits a higher affinity for CD226 than CD112 [8]. CD112 and CD155 exhibit expression across a wide range of cell types, including antigen-presenting cells, epithelial cells, fibroblasts, endothelial cells, neurons, pathogen-infected cells, and numerous types of cancer cells [9,10]. Notably, CD112 and CD155 also engage inhibitory receptor T cell immunoreceptor with Ig and ITIM domains (TIGIT), creating a competitive axis where CD226’s lower ligand affinity allows for dynamic immune regulation [11]. The opposing signaling of CD226 and TIGIT upon engagement with their shared ligands is illustrated in Figure 1. Upon ligand binding to CD155 or CD112, protein kinase C (PKC) phosphorylates the S329 residue of CD226, enabling its association with lymphocyte function-associated antigen-1 (LFA-1) [12]. This interaction facilitates the subsequent phosphorylation of the Y322 residue by the Src family kinase Fyn [13]. The activated CD226 initiates downstream signaling through the phosphorylation of vav guanine nucleotide exchange factor 1 (Vav1) and lymphocyte cytosolic protein 2 (LCP2), which stimulate phospholipase C gamma 2 (PLCγ2) activity. Consequently, extracellular signal-regulated kinase (ERK) and protein kinase B (PKB/AKT) are activated [2], thereby driving calcium mobilization and degranulation—critical processes for effector cell functions [1]. The strategic positioning of CD226 within this ligand–receptor network underscores its role as a pivotal immune checkpoint. The dysregulation of CD226 signaling—through genetic polymorphisms, altered expression, or imbalanced ligand interactions—disrupts immune homeostasis and is mechanistically linked to aberrant inflammation, autoimmunity, and impaired pathogen/tumor surveillance. Consequently, understanding CD226’s molecular interactions is essential for deciphering its pathophysiological roles in immune-mediated diseases.

2. Effects of CD226 in Immune Cells

2.1. CD226 and T Cells

CD226 serves as an important regulator governing the maturation and differentiation of T cells. During thymocyte development, CD226 expression increases from the double-positive to single-positive stages, with a higher expression level in CD8+ T cells. CD226 deficiency impairs T cell receptor signaling by reducing p38, AKT, ERK, and nuclear factor-kappa B (NF-κB) phosphorylation, leading to enhanced apoptosis [14]. Upon engagement, CD226 induces tyrosine phosphorylation of VAV1, which subsequently amplifies T cell receptor (TCR)-driven ERK activation and specifically promotes interleukin (IL)-17 production in CD4+ T cells [15]. The CD155-CD226 interaction further modulates memory-like CD8+ T cell generation in the thymus by regulating IL-4 levels and invariant NKT (iNKT) cell differentiation [16,17]. CD226 drives the differentiation of proinflammatory T helper (Th) subsets. It promotes Th17 and Th1 polarization by enhancing IL-17 and IFN-γ production, while its knockdown or blockade shifts the balance toward Th2 responses (elevated IL-4 and IL-13) [18,19]. CD226 also facilitates LFA-1-mediated costimulation in naive T cells, supporting Th1 differentiation and proliferation [20]. In T follicular helper (Tfh) cells, CD226 promotes early differentiation and proliferation, while its role diminishes in mature germinal center-Tfh cells [21]. These findings highlight CD226’s critical role in shaping the T cell repertoire and ensuring functional competence.
CD226 polymorphisms influence T cell function and disease susceptibility. The CD226-307Ser risk variant enhances interferon-γ (IFN-γ) signaling in CD8+ T cells via increased ERK1/2 and signal transducer and activator of transcription (STAT) 4 phosphorylation, contributing to chronic inflammation in conditions like multiple sclerosis [22]. Additionally, the TT genotype of rs763361 reduces CD226 expression on T cells while elevating IL-17A secretion, linking it to autoimmune dysregulation [15,23].
In contrast to conventional CD4+ T cells, CD226 exhibits more intricate functions in regulatory T cells (Tregs). Several studies have shown that CD226 impairs Treg stability and immunosuppressive capacity. Studies in murine models demonstrate that CD226 deficiency in Tregs alleviates insulitis and delays diabetes onset in non-obese diabetic (NOD) mice, suggesting a suppressive function for CD226 in Treg-mediated tolerance during autoimmunity [24]. Similarly, Sato K et al. found that deficiency in CD226 potentiates TIGIT-mediated signaling in Tregs, which maintains Treg cell function and forkhead box P3 (Foxp3) expression in the context of inflammatory settings [25]. However, some studies have come to the opposite conclusion. CD226 is found to play roles in maintaining Treg metabolic fitness and lineage stability via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/myelocytomatosis oncogene (Myc) axis [26], and its deficiency impairs Treg immunosuppressive function and induces apoptosis, thereby exacerbating inflammatory responses [27,28]. In T regulatory type 1 cells, CD226 supports proliferation, survival, and IL-10 production, essential for immune tolerance, while CD226 deficiency impairs T regulatory type 1 cell differentiation and STAT5 signaling [29]. These divergent roles of CD226 in different T cell subsets underscore the critical influence of immune cell heterogeneity on therapeutic outcomes, necessitating cell-specific targeting strategies tailored to distinct disease mechanisms and functional pathways.

2.2. CD226 and NK Cells

CD226 plays a critical role in the activation and cytotoxic function of NK cells, significantly influencing immune responses against target cells. CD226 enhances NK cell effector functions by facilitating stable interactions with target cells [30]. Its first extracellular domain binds to CD155 and CD112, promoting immune synapse formation and cytotoxicity. Blocking the first extracellular domain disrupts NK cell activation, reducing granule polarization and target cell killing [31]. Mechanistically, CD226 signals through a conserved cytoplasmic motif that recruits Grb2 and activates downstream pathways, including Vav1, PI3K, and phospholipase C gamma 1 (PLC-γ1), leading to actin polymerization and cytotoxic granule release [2]. Additionally, CD226 mediates functional suppression of the transcription factor forkhead box protein O1 (FOXO1), amplifying NK cell cytotoxicity against tumors [32]. Transcriptional profiling and functional studies identifies two NK cell subsets defined by CD226 expression: CD226+ NK cells, which exhibit enhanced proliferative activity accompanied by abundant inflammatory cytokine secretion; and CD226− NK cells, which produce higher levels of macrophage inflammatory protein 1. This indicates a CD226-defined axis governing NK cell maturation [33]. In addition, CD226 contributes to the modulation of NK cell education, a process shaped by major histocompatibility complex class I (MHC-I) interactions with inhibitory receptors. Upon target cell recognition, CD226 and LFA-1 rapidly colocalize at the immune synapse, indicating that their coordinated expression is crucial for NK cell education [34]. Notably, CD226 orchestrates NK cell antitumor efficacy by sustaining cytotoxic effector functions and stabilizing immune synapses with malignant cells, making it a pivotal node in cancer immune surveillance. CD226-deficient NK cells exhibit impaired tumor control due to shortened contact durations with cancer cells and reduced cytotoxicity, and antibodies blocking CD226-CD155 interactions suppress NK cell-mediated cytotoxicity [30,35]. Strategies to enhance CD226 signaling can bolster NK cell antitumor activity [32], highlighting CD226 as a promising candidate for cancer immunotherapeutic approaches. While sex hormones are known to modulate various aspects of NK cell function [36], their specific impact on CD226 expression or activity remains unexplored. The potential influence of gender or hormonal status on CD226-mediated NK cell responses represents an intriguing area for future investigation as it could offer valuable insights into observed sex-specific differences in disease susceptibility and therapeutic outcomes involving this pathway.

2.3. CD226 and Other Immune Cells

In contrast to its extensively documented functions in T and NK cells, its immunological regulation and effector mechanisms in other immune cell types remain insufficiently explored. CD226 is expressed in macrophage and plays a role in regulating macrophage polarization. CD226 deletion promotes M2 macrophage polarization and inhibits M1 macrophage accumulation, leading to improved post-infarction healing [37]. In obesity, CD226 deficiency in macrophages suppresses phosphorylation of VAV1 and AKT, leading to reduced FOXO1 inactivation. This results in enhanced FOXO1-dependent peroxisome proliferator-activated receptor gamma (PPARγ) expression, which inhibits pro-inflammatory M1 polarization [38]. CD226 expression in macrophages is upregulated during renal fibrogenesis, and its deficiency reduces collagen deposition and pro-inflammatory responses in the kidney. Mechanistically, CD226 promotes M1 macrophage accumulation by suppressing kruppel-like factor 4 (KLF4) expression [39]. In B cells, CD226 is selectively expressed on differentiated subsets, including class-switched memory B cells, plasmablasts, and plasma cells. Upon CpG-ODN (TLR9 agonist) stimulation, CD226 expression is upregulated and functionally contributes to enhanced IL-10 secretion and antibody production in these B cell subsets [40]. A summary of the key effects of CD226 on immune cell function is presented in Table 1.

3. The Roles of CD226 in Immune-Mediated Disorders

3.1. CD226 and Tumors

3.1.1. CD226 Expression and Prognostic Significance

Elevated CD226 levels in tumor-infiltrating lymphocytes demonstrate a positive association with enhanced anti-tumor activity and favorable prognostic outcomes. In gastric cancer, high CD226+CD8+ T cell infiltration predicts better survival and response to adjuvant chemotherapy [41,42]. Similarly, CD226 expression on CD8+ tumor-infiltrating lymphocytes from colorectal cancer liver metastases serves as an independent prognostic factor, associated with better survival outcomes. IL-15 treatment restores CD226 expression on CD8+ TILs, enhancing their functionality and providing a potential therapeutic target [43]. In addition, reduced CD226 expression on peripheral NK cells or tumor-infiltrating lymphocytes is correlated with tumor progression, resistance to immunotherapy, and poor prognosis in gastric cancer, hepatocellular carcinoma, acute myeloid leukemia, pancreatic cancer, melanoma, neuroblastoma, and chronic lymphocytic leukemia [44,45,46,47,48,49,50,51]. Analysis via single-cell sequencing shows that effector CD4+ T cells exhibit increased CD226 expression compared to naïve CD4+ T cells, while exhausted CD8+ T cells display reduced CD226 expression relative to effector CD8+ T cells among various types of tumors [52]. Flow cytometry in murine B16F10 melanoma models shows strong correlations between CD226 and the activities of tumor-infiltrating CD8+ T cells and NK cells, while gene set enrichment analysis highlights its links to T cell activation, T cell receptor signaling, NK cell-mediated immune responses and cytotoxicity [52]. In addition, CD226 polymorphisms influence cancer risk and treatment outcomes. The rs727088 G allele and rs763361 T allele are correlated with increased susceptibility to gastric cancer and non-small-cell lung cancer [53,54]. In small-cell lung cancer, CD226 rs763361C>T is associated with better chemotherapy response [55].

3.1.2. CD226 and Immune Checkpoint Interactions

The dynamic equilibrium between CD226 and TIGIT modulates effector functions of immune cells, dictating distinct functional outcomes. In tumors where CD226 and TIGIT are not co-expressed, TIGIT dominates via ligand-induced nanoclustering, suppressing cytokine secretion and T cell activation [56]. CD226highCD8+ T cells exhibit greater responsiveness and self-renewal at tumor sites, and anti-TIGIT treatment enhances their function by promoting CD226 phosphorylation [57]. In melanoma, Tregs exhibit an elevated TIGIT/CD226 ratio, correlating with higher tumor-infiltrating Treg levels and worse clinical prognosis [58]. Similarly, Jin et al. reported an imbalance between CD226 and TIGIT expression on γδ T cells in acute myeloid leukemia patients, with a reduction in CD226+ γδ T cells and an increase in TIGIT+ γδ T cells, suggesting a potential immune checkpoint barrier contributing to poor prognosis and T cell dysfunction [59].

3.1.3. CD226 in Tumor Immune Evasion

CD226 emerges as a critical immune checkpoint in antitumor immunity, yet tumors subvert its function through CD155-driven degradation mechanisms, enabling evasion of both adaptive and innate immune surveillance. CD155 on tumor cells induces CD226 degradation via phosphorylation and ubiquitination, impairing CD8+ T cell function and immunotherapy efficacy [60]. Acute myeloid leukemia blasts reduce CD226 expression on NK cells, suggesting a mechanism of tumor escape by impairing the cytotoxicity of NK cells [47]. Similarly, CD155-expressing hepatocellular carcinoma cells induce CD226 downregulation, impairing CD226-mediated cytotoxicity in both tumor-infiltrating and circulating NK cells, which contributes to the tumor evasion of innate immune surveillance [61].

3.1.4. CD226 as a Therapeutic Target

Emerging preclinical evidence positions CD226 activation as a pivotal amplifier of anti-tumor immunity, synergizing with chemotherapy, immune checkpoint blockade, and vaccine strategies to enhance NK/cytotoxic T lymphocyte (CTL) cytotoxicity across diverse malignancies. In multiple myeloma, CD226 limits spontaneous multiple myeloma development and enhances the efficacy of treatment with cyclophosphamide and bortezomib [62]. CD226 activation or overexpression enhances NK cell cytotoxicity—via granzyme B secretion, apoptosis induction, and efficient degranulation—against diverse malignancies, including triple-negative breast cancer and sarcomas [63,64]. Anti-programmed cell death protein-1 (PD-1) treatment enhances the CD155-CD226 activation pathway, improving NK cell function and inhibiting tumor proliferation [44]. A tumor vaccine expressing both CD226 and Ag85A induces stronger antitumor immunity in a colon carcinoma model, enhancing NK and CTL cytotoxicity and increasing IFN-γ-producing T cells. This suggests that CD226 acts as a genetic adjuvant, synergistically boosting the efficacy of the Ag85A vaccine against colon cancer [65]. Moreover, soluble CD226 exhibit cytotoxic activity against CD155-expressing tumor cells, suggesting its potential as a biotherapeutic agent [66,67]. Exosomes derived from IL-2/IL-15-treated NK cells carry CD226, enabling cytolytic activity at tumor sites and offering a novel immunotherapy strategy [68]. These extensive preclinical evidence underscores CD226’s potential as a promising therapeutic target for cancer immunotherapy.

3.2. CD226 and Infectious Diseases

CD226 expression on immune cells is dynamically regulated during infections and correlates with immune responses. In Hantaan virus infection, reduced CD226 expression on inflammatory monocytes is associated with impaired antigen presentation (e.g., CD80 and HLA-DQ/DR/DP downregulation), increased viral load, and disease severity [69]. In latent tuberculosis infection, memory-like NK cells exhibit elevated CD226 expression, which drives their proliferation and effector functions [70]. Similarly, tuberculosis patients show increased CD226+ NK and T cell subsets with enhanced production of CD107a and IFN-γ, suggesting CD226 as a biomarker for clinical outcomes and disease progression in tuberculosis [71]. In addition, CD226 polymorphisms influence host susceptibility and disease severity. The rs763362 G/rs727088 G/rs763361 T alleles are linked to severe influenza infections, with higher hospitalization rates in intensive care units. These variants may impair NK cell responses to influenza, exacerbating disease outcomes [72].
Similar to tumor cells, viruses can also exploit CD226-mediated pathways to evade immune surveillance. Human immunodeficiency virus (HIV) persistent infection skews the CD226/TIGIT axis toward TIGIT dominance, suppressing CD8+ T cell function. Reduces CD226 expression on CD8+ T cells contributes to T cell exhaustion and persistent viral replication, underscoring its role as a checkpoint barrier in HIV cure strategies [73,74]. CD226 blockade significantly compromises the proliferation of Ly49H+ NK cells specific for mouse cytomegalovirus and impairs memory NK cell development, while CD226-deficient NK cells shows similar defects [75]. Lymphocytic choriomeningitis virus-infected CD226-deficient mice show delayed viral clearance due to reduced tumor necrosis factor-α (TNF-α) and IL-2 secretion by CD8+ T cells, despite intact cytolytic activity [76]. These mechanisms illustrate how pathogens manipulate CD226 to subvert host immunity and how targeting CD226 pathways offers potential strategies to enhance infection control.

3.3. CD226 and Allergic Diseases

CD226 plays roles in driving inflammatory responses across diverse immune cells in a variety of inflammatory diseases. CD226 is upregulated in activated CD4+ T cells (Th2/Th17 subsets) and type 2 innate lymphoid cells (ILC2s) in asthma patients, enhancing airway hyperreactivity and inflammation. Targeting CD226 reduces ILC2-mediated cytokine secretion (e.g., IL-5, IL-13) and promotes CD4+ T cell apoptosis via Caspase-3 activation, ameliorating lung inflammation and airway remodeling in preclinical models [77,78]. In addition, the deficiency of CD226 expression in CD4+ T cells alleviates lung inflammation and increases IL-10 levels in ovalbumin-induced allergic asthma [79]. In a murine model of allergic rhinitis, global CD226 knockout mice exhibited reduced nasal symptoms and inflammatory responses, with significant decreases in Th2-inflammatory cytokines, eosinophil recruitment, and goblet cell proliferation [80].

3.4. CD226 and Autoimmune Diseases

3.4.1. Rheumatoid Arthritis

CD226 polymorphisms, particularly the rs763361 (Gly307Ser) variant, are significantly associated with rheumatoid arthritis susceptibility across diverse ethnic populations, including Chinese Han, Iranian, and Egyptian cohorts [81,82,83]. Serum soluble CD226 levels correlate with rheumatoid arthritis disease activity, suggesting its utility as a biomarker [81]. Notably, the rs763361 T allele is linked to reduced anti-TNF treatment efficacy, underscoring its potential role in personalized therapeutic strategies [84]. However, CD226 blockade showed limited efficacy in a collagen-induced arthritis murine model [85].

3.4.2. Systemic Lupus Erythematosus

Elevated serum soluble CD226 levels are observed in active systemic lupus erythematosus and correlate with disease activity indices and anti-dsDNA antibody titers, positioning soluble CD226 as a biomarker to monitor disease flares [86]. CD226+ B cells, particularly switched-memory subsets, are increased in systemic lupus erythematosus patients and correlated with higher disease activity [87]. Additionally, the CD226 rs763361 polymorphism is linked to elevated risk of systemic lupus erythematosus, particularly in Chinese Han populations [88]. However, CD226+ NK cells are deficient in active systemic lupus erythematosus, potentially due to activation-induced cell death [89].

3.4.3. Systemic Sclerosis

In systemic sclerosis patients’ skin tissue, CD226 overexpression exacerbates fibrotic progression by enhancing T cell infiltration and prompting the secretion of pro-inflammatory cytokines including TNF-α and IL-6 [90]. In systemic sclerosis patients, elevated CD226 expression in CD8+ T cells promotes profibrotic IL-13 production and endothelial damage [91]. Murine studies demonstrate that CD226 neutralization reduces dermal fibrosis by suppressing cytokine production and T cell activation [90]. Genome-wide association analyses in European ancestry cohorts have identified the CD226 rs763361 T allele as a genetic risk locus for systemic sclerosis, demonstrating particularly strong associations with severe clinical phenotypes including diffuse cutaneous involvement [92]. However, CD226 polymorphisms demonstrate no significant association with systemic sclerosis susceptibility in Iranian populations, highlighting ethnic variability in genetic risk [93].

3.4.4. Primary Sjögren’s Syndrome

In primary Sjögren’s syndrome, CD226 expression is significantly altered in immune cells. Elevated frequencies of CD4+ T cells with CD226 and TIGIT expression show significant association with clinical disease severity, suggesting their potential as therapeutic targets [94]. Additionally, increased proportions of CD226+CD14+ monocytes have been reported in primary Sjögren’s syndrome patients, correlating with the severity of the disease [95]. Intriguingly, plasma soluble CD226 levels are reduced in primary Sjögren’s syndrome and inversely correlate with clinical manifestations and disease progression, indicating its diagnostic potential [96].

3.4.5. Type 1 Diabetes

Genetic research has identified the CD226 rs763361 polymorphism as a risk factor for type 1 diabetes, particularly in Chinese Han children and Brazilian populations [97,98]. Functional studies in NOD mice models have shown that CD226 deficiency or blockade delays insulitis onset and reduces diabetes incidence by inhibiting effector T cell activation and enhancing Treg function [99,100]. CD226+ CD8+ T cell subsets exhibit a enhanced cytotoxic activity and are inversely correlated with β-cell function. CD226 blockade delays the onset of insulitis and mitigates the severity of hyperglycemia in both streptozotocin-induced and cyclophosphamide-induced murine diabetes models [101].

3.4.6. Multiple Sclerosis and Neuromyelitis Optica

An increase in soluble CD226 levels has been detected in multiple sclerosis and neuromyelitis optica patients, correlating with neuroinflammation and disease progression [102]. CD226 deficiency in experimental autoimmune encephalomyelitis models reduces Th17 infiltration and increases Treg suppressive capacity, attenuating disease severity [103,104,105]. In neuromyelitis optica, CD226 overexpression on T regulatory type 1 cells correlates with disease severity, suggesting its role as a progression biomarker [106]. The CD226 Gly307Ser (rs763361) polymorphism is correlated with a higher risk of neuromyelitis optica in Southern Han Chinese, but not with multiple sclerosis [107].

3.4.7. Other Autoimmune Diseases

Antiphospholipid syndrome (APS) is a complex autoimmune disorder characterized by the presence of antiphospholipid antibodies [108]. These antibodies initiate signaling through receptors like toll-like receptor 4 (TLR4), low-density lipoprotein receptor-related protein (LRP) 6, and LRP8, and this process relies on lipid rafts—cholesterol- and sphingolipid-rich microdomains within the plasma membrane [108,109]. Notably, CD226 has been reported to localize within lipid rafts [110], and this spatial co-localization strongly implies a potential mechanistic link between APS and CD226 function. Exploring whether CD226 function and localization depend on lipid raft integrity could open new avenues for understanding APS pathogenesis. Methyl-β-cyclodextrin, with its ability to selectively disassemble lipid rafts [109], is a valuable experimental tool. In addition, the imbalance in the expression of CD226/TIGIT in NK cells is associated with antiphospholipid syndrome progression and autoantibody status, suggesting a potential therapeutic target [111].
Furthermore, CD226 has also been found to play roles in other autoimmune diseases. The CD226 rs763361 polymorphism demonstrates a significant correlation with increased risk of juvenile idiopathic arthritis across various subtypes [112]. Enhanced activation of the CD155-CD226 signaling pathway is observed in inflamed muscle tissues of patients with idiopathic inflammatory myopathies, correlating with disease severity and muscle damage [113]. Furthermore, the CD226 rs763361 polymorphism is linked to higher susceptibility to autoimmune thyroid disease and psoriasis [114,115]. These findings highlight the broad role of CD226 in autoimmune pathogenesis. The multifaceted roles of CD226 in the pathogenesis and progression of various immune-mediated disorders are summarized in Table 2.

4. Perspectives

The extensive role of CD226 in immune regulation underscores its therapeutic potential and complexity. The dual functionality of CD226 in Treg functionality highlights its complex contribution to immune dysregulation and underscores the need for cell-specific targeting strategies. Future research should delve deeper into the molecular mechanisms underlying CD226’s diverse functions in different immune cell types and such understanding will contribute to the development of more targeted therapeutic interventions. CD226 polymorphisms significantly impact disease susceptibility and progression, highlighting the potential of personalized medicine approaches targeting CD226. Additionally, developing precise therapeutic interventions that target CD226’s context-dependent functions without causing systemic immune dysregulation remains a critical challenge. Combining CD226-targeted therapies with existing immunotherapies may also offer synergistic benefits, warranting further exploration in clinical settings.

Author Contributions

K.L. and Y.L. were responsible for writing the initial draft. H.X. and Z.N. contributed to funding acquisition and manuscript editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Doctoral Startup Fund of Jining Medical University (2017JYQD24).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. de Andrade, L.F.; Smyth, M.J.; Martinet, L. DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins. Immunol. Cell Biol. 2014, 92, 237–244. [Google Scholar] [CrossRef] [PubMed]
  2. Zhang, Z.; Wu, N.; Lu, Y.; Davidson, D.; Colonna, M.; Veillette, A. DNAM-1 controls NK cell activation via an ITT-like motif. J. Exp. Med. 2015, 212, 2165–2182. [Google Scholar] [CrossRef]
  3. Liu, J.; Qian, X.; Chen, Z.; Xu, X.; Gao, F.; Zhang, S.; Zhang, R.; Qi, J.; Gao, G.F.; Yan, J. Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J. Immunol. 2012, 188, 5511–5520. [Google Scholar] [CrossRef]
  4. Shibuya, A.; Campbell, D.; Hannum, C.; Yssel, H.; Franz-Bacon, K.; McClanahan, T.; Kitamura, T.; Nicholl, J.; Sutherland, G.R.; Lanier, L.L.; et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 1996, 4, 573–581. [Google Scholar] [CrossRef]
  5. Wang, H.; Qi, J.; Zhang, S.; Li, Y.; Tan, S.; Gao, G.F. Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5. Proc. Natl. Acad. Sci. USA 2019, 116, 988–996. [Google Scholar] [CrossRef] [PubMed]
  6. Kojima, H.; Kanada, H.; Shimizu, S.; Kasama, E.; Shibuya, K.; Nakauchi, H.; Nagasawa, T.; Shibuya, A. CD226 mediates platelet and megakaryocytic cell adhesion to vascular endothelial cells. J. Biol. Chem. 2003, 278, 36748–36753. [Google Scholar] [CrossRef]
  7. Bachelet, I.; Munitz, A.; Mankutad, D.; Levi-Schaffer, F. Mast cell costimulation by CD226/CD112 (DNAM-1/Nectin-2): A novel interface in the allergic process. J. Biol. Chem. 2006, 281, 27190–27196. [Google Scholar] [CrossRef] [PubMed]
  8. Seth, S.; Georgoudaki, A.M.; Chambers, B.J.; Qiu, Q.; Kremmer, E.; Maier, M.K.; Czeloth, N.; Ravens, I.; Foerster, R.; Bernhardt, G. Heterogeneous expression of the adhesion receptor CD226 on murine NK and T cells and its function in NK-mediated killing of immature dendritic cells. J. Leukoc. Biol. 2009, 86, 91–101. [Google Scholar] [CrossRef]
  9. Kraus, A.K.; Chen, J.; Edenhofer, I.; Ravens, I.; Gaspert, A.; Cippa, P.E.; Mueller, S.; Wuthrich, R.P.; Segerer, S.; Bernhardt, G.; et al. The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation. PLoS ONE 2016, 11, e0147951. [Google Scholar] [CrossRef]
  10. Gilfillan, S.; Chan, C.J.; Cella, M.; Haynes, N.M.; Rapaport, A.S.; Boles, K.S.; Andrews, D.M.; Smyth, M.J.; Colonna, M. DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors. J. Exp. Med. 2008, 205, 2965–2973. [Google Scholar] [CrossRef]
  11. Zeng, T.; Cao, Y.; Jin, T.; Tian, Y.; Dai, C.; Xu, F. The CD112R/CD112 axis: A breakthrough in cancer immunotherapy. J. Exp. Clin. Cancer Res. 2021, 40, 285. [Google Scholar] [CrossRef]
  12. Shibuya, A.; Lanier, L.L.; Phillips, J.H. Protein kinase C is involved in the regulation of both signaling and adhesion mediated by DNAX accessory molecule-1 receptor. J. Immunol. 1998, 161, 1671–1676. [Google Scholar] [CrossRef] [PubMed]
  13. Shibuya, K.; Lanier, L.L.; Phillips, J.H.; Ochs, H.D.; Shimizu, K.; Nakayama, E.; Nakauchi, H.; Shibuya, A. Physical and functional association of LFA-1 with DNAM-1 adhesion molecule. Immunity 1999, 11, 615–623. [Google Scholar] [CrossRef] [PubMed]
  14. Ma, J.; Liu, Y.; Duan, C.; Wu, S.; Xie, Y.; Yang, L.; Li, X.; Wang, Y.; Zhang, Y.; Zhuang, R. CD226 knockout reduces the development of CD8+ T by impairing the TCR sensitivity of double-positive thymocytes. Immunology 2023, 169, 83–95. [Google Scholar] [CrossRef] [PubMed]
  15. Gaud, G.; Roncagalli, R.; Chaoui, K.; Bernard, I.; Familiades, J.; Colacios, C.; Kassem, S.; Monsarrat, B.; Burlet-Schiltz, O.; de Peredo, A.G.; et al. The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4(+) T cells. Sci. Signal. 2018, 11, eaar3083. [Google Scholar] [CrossRef]
  16. Georgiev, H.; Ravens, I.; Shibuya, A.; Forster, R.; Bernhardt, G. CD155/CD226-interaction impacts on the generation of innate CD8(+) thymocytes by regulating iNKT-cell differentiation. Eur. J. Immunol. 2016, 46, 993–1003. [Google Scholar] [CrossRef]
  17. Danisch, S.; Qiu, Q.; Seth, S.; Ravens, I.; Dorsch, M.; Shibuya, A.; Shibuya, K.; Forster, R.; Bernhardt, G. CD226 interaction with CD155 impacts on retention and negative selection of CD8 positive thymocytes as well as T cell differentiation to follicular helper cells in Peyer’s Patches. Immunobiology 2013, 218, 152–158. [Google Scholar] [CrossRef]
  18. Lozano, E.; Joller, N.; Cao, Y.; Kuchroo, V.K.; Hafler, D.A. The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance in humans. J. Immunol. 2013, 191, 3673–3680. [Google Scholar] [CrossRef]
  19. Dardalhon, V.; Schubart, A.S.; Reddy, J.; Meyers, J.H.; Monney, L.; Sabatos, C.A.; Ahuja, R.; Nguyen, K.; Freeman, G.J.; Greenfield, E.A.; et al. CD226 is specifically expressed on the surface of Th1 cells and regulates their expansion and effector functions. J. Immunol. 2005, 175, 1558–1565. [Google Scholar] [CrossRef]
  20. Shibuya, K.; Shirakawa, J.; Kameyama, T.; Honda, S.; Tahara-Hanaoka, S.; Miyamoto, A.; Onodera, M.; Sumida, T.; Nakauchi, H.; Miyoshi, H.; et al. CD226 (DNAM-1) is involved in lymphocyte function-associated antigen 1 costimulatory signal for naive T cell differentiation and proliferation. J. Exp. Med. 2003, 198, 1829–1839. [Google Scholar] [CrossRef]
  21. Yasutomi, M.; Christiaansen, A.F.; Imai, N.; Martin-Orozco, N.; Forst, C.V.; Chen, G.; Ueno, H. CD226 and TIGIT Cooperate in the Differentiation and Maturation of Human Tfh Cells. Front. Immunol. 2022, 13, 840457. [Google Scholar] [CrossRef]
  22. Morandi, E.; Adoue, V.; Bernard, I.; Friebel, E.; Nunez, N.; Aubert, Y.; Masson, F.; Dejean, A.S.; Becher, B.; Astier, A.; et al. Impact of the Multiple Sclerosis-Associated Genetic Variant CD226 Gly307Ser on Human CD8 T-Cell Functions. Neurol. (R) Neuroimmunol. Neuroinflamm. 2024, 11, e200306. [Google Scholar] [CrossRef] [PubMed]
  23. Sunina, M.; Alnek, K.; Kisand, K.; Uibo, R. Human CD4(+) and CD8(+) T lymphocyte subpopulations have significantly different surface expression patterns of CD226 and TIGIT molecules. Scand. J. Immunol. 2021, 94, e13089. [Google Scholar] [CrossRef]
  24. Thirawatananond, P.; Brown, M.E.; Sachs, L.K.; Arnoletti, J.M.; Yeh, W.I.; Posgai, A.L.; Shapiro, M.R.; Chen, Y.G.; Brusko, T.M. Treg-Specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T-Cell Stability. Diabetes 2023, 72, 1629–1640. [Google Scholar] [CrossRef] [PubMed]
  25. Sato, K.; Yamashita-Kanemaru, Y.; Abe, F.; Murata, R.; Nakamura-Shinya, Y.; Kanemaru, K.; Muratani, M.; Veillette, A.; Goto, M.; Ito, M.; et al. DNAM-1 regulates Foxp3 expression in regulatory T cells by interfering with TIGIT under inflammatory conditions. Proc. Natl. Acad. Sci. USA 2021, 118, e2021309118. [Google Scholar] [CrossRef]
  26. Ma, J.; Hu, W.; Liu, Y.; Duan, C.; Zhang, D.; Wang, Y.; Cheng, K.; Yang, L.; Wu, S.; Jin, B.; et al. CD226 maintains regulatory T cell phenotype stability and metabolism by the mTOR/Myc pathway under inflammatory conditions. Cell Rep. 2023, 42, 113306. [Google Scholar] [CrossRef] [PubMed]
  27. Qiao, W.; Duan, C.; Ma, J.; Hu, W.; Xie, Y.; Yang, L.; Wang, T.; Wu, S.; Li, X.; Wang, Y.; et al. Costimulatory Molecule CD226 Regulates Atopic Dermatitis in a Mouse Model. J. Investig. Dermatol. 2024, 144, 1743–1753. [Google Scholar] [CrossRef]
  28. Wang, T.; Qiao, W.; Xie, Y.; Ma, J.; Hu, W.; Yang, L.; Li, X.; Duan, C.; Wu, S.; Wang, Y.; et al. CD226 deficiency exacerbated intestinal immune dysregulation in mice with dinitrochlorobenzene-induced atopic dermatitis. Immunology 2023, 169, 431–446. [Google Scholar] [CrossRef]
  29. Wang, N.; Chen, P.; Song, Y.; Shen, Y.; Li, J.; Li, X.; Fang, L.; Chen, L. CD226 deficiency attenuates the homeostasis and suppressive capacity of Tr1 cells. Mol. Immunol. 2021, 132, 192–198. [Google Scholar] [CrossRef]
  30. Kim, J.S.; Shin, B.R.; Lee, H.K.; Lee, J.H.; Kim, K.H.; Choi, J.E.; Ji, A.Y.; Hong, J.T.; Kim, Y.; Han, S.B. Cd226(-/-) natural killer cells fail to establish stable contacts with cancer cells and show impaired control of tumor metastasis in vivo. Oncoimmunology 2017, 6, e1338994. [Google Scholar] [CrossRef]
  31. Hou, S.; Ge, K.; Zheng, X.; Wei, H.; Sun, R.; Tian, Z. CD226 protein is involved in immune synapse formation and triggers Natural Killer (NK) cell activation via its first extracellular domain. J. Biol. Chem. 2014, 289, 6969–6977. [Google Scholar] [CrossRef] [PubMed]
  32. Du, X.; de Almeida, P.; Manieri, N.; de Almeida Nagata, D.; Wu, T.D.; Harden Bowles, K.; Arumugam, V.; Schartner, J.; Cubas, R.; Mittman, S.; et al. CD226 regulates natural killer cell antitumor responses via phosphorylation-mediated inactivation of transcription factor FOXO1. Proc. Natl. Acad. Sci. USA 2018, 115, E11731–E11740. [Google Scholar] [CrossRef]
  33. Martinet, L.; Ferrari De Andrade, L.; Guillerey, C.; Lee, J.S.; Liu, J.; Souza-Fonseca-Guimaraes, F.; Hutchinson, D.S.; Kolesnik, T.B.; Nicholson, S.E.; Huntington, N.D.; et al. DNAM-1 expression marks an alternative program of NK cell maturation. Cell Rep. 2015, 11, 85–97. [Google Scholar] [CrossRef]
  34. Enqvist, M.; Ask, E.H.; Forslund, E.; Carlsten, M.; Abrahamsen, G.; Beziat, V.; Andersson, S.; Schaffer, M.; Spurkland, A.; Bryceson, Y.; et al. Coordinated expression of DNAM-1 and LFA-1 in educated NK cells. J. Immunol. 2015, 194, 4518–4527. [Google Scholar] [CrossRef] [PubMed]
  35. Iguchi-Manaka, A.; Kai, H.; Yamashita, Y.; Shibata, K.; Tahara-Hanaoka, S.; Honda, S.; Yasui, T.; Kikutani, H.; Shibuya, K.; Shibuya, A. Accelerated tumor growth in mice deficient in DNAM-1 receptor. J. Exp. Med. 2008, 205, 2959–2964. [Google Scholar] [CrossRef]
  36. Byemerwa, J.; Chang, C.Y.; McDonnell, D.P. The Roles of Natural Killer Cells in Breast Cancer Pathobiology and their Regulation by Estrogens. Endocr. Rev. 2025, bnaf014. [Google Scholar] [CrossRef] [PubMed]
  37. Li, J.; Song, Y.; Jin, J.Y.; Li, G.H.; Guo, Y.Z.; Yi, H.Y.; Zhang, J.R.; Lu, Y.J.; Zhang, J.L.; Li, C.Y.; et al. CD226 deletion improves post-infarction healing via modulating macrophage polarization in mice. Theranostics 2020, 10, 2422–2435. [Google Scholar] [CrossRef]
  38. Ma, J.; Hu, W.; Zhang, D.; Xie, J.; Duan, C.; Liu, Y.; Wang, Y.; Xu, X.; Cheng, K.; Jin, B.; et al. CD226 knockout alleviates high-fat diet induced obesity by suppressing proinflammatory macrophage phenotype. J. Transl. Med. 2021, 19, 477. [Google Scholar] [CrossRef]
  39. Song, Y.; Wang, Y.; Li, J.; Shen, Y.; Hou, Y.; Fu, Z.; Fang, L.; Jin, B.; Chen, L. CD226 promotes renal fibrosis by regulating macrophage activation and migration. J. Leukoc. Biol. 2024, 116, 103–117. [Google Scholar] [CrossRef]
  40. Nagayama-Hasegawa, Y.; Honda, S.I.; Shibuya, A.; Shibuya, K. Expression and function of DNAM-1 on human B-lineage cells. Cytom. Part B Clin. Cytom. 2020, 98, 368–374. [Google Scholar] [CrossRef]
  41. Huang, H.; Huang, Z.; Ge, J.; Yang, J.; Chen, J.; Xu, B.; Wu, S.; Zheng, X.; Chen, L.; Zhang, X.; et al. CD226 identifies functional CD8(+)T cells in the tumor microenvironment and predicts a better outcome for human gastric cancer. Front. Immunol. 2023, 14, 1150803. [Google Scholar] [CrossRef]
  42. Zhang, Y.; Zhao, Z.X.; Gao, J.P.; Huang, Y.K.; Huang, H. Tumor-infiltrating CD226(+)CD8(+) T cells are associated with postoperative prognosis and adjuvant chemotherapeutic benefits in gastric cancer patients. J. Cancer Res. Clin. Oncol. 2023, 149, 4381–4389. [Google Scholar] [CrossRef] [PubMed]
  43. Viot, J.; Abdeljaoued, S.; Vienot, A.; Seffar, E.; Spehner, L.; Bouard, A.; Asgarov, K.; Pallandre, J.R.; Renaude, E.; Klajer, E.; et al. CD8(+) CD226(high) T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery. Cell. Mol. Immunol. 2023, 20, 365–378. [Google Scholar] [CrossRef] [PubMed]
  44. Wang, J.; Yang, L.; Wang, H.X.; Cui, S.P.; Gao, Y.; Hu, B.; Zhou, L.; Lang, R. Anti-PD-1 therapy reverses TIGIT(+)CD226(+)NK depletion in immunotherapy resistance of hepatocellular carcinoma through PVR/TIGIT pathway. Int. Immunopharmacol. 2024, 130, 111681. [Google Scholar] [CrossRef] [PubMed]
  45. Weulersse, M.; Asrir, A.; Pichler, A.C.; Lemaitre, L.; Braun, M.; Carrie, N.; Joubert, M.V.; Le Moine, M.; Do Souto, L.; Gaud, G.; et al. Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8(+) T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy. Immunity 2020, 53, 824–839.e10. [Google Scholar] [CrossRef] [PubMed]
  46. Guillamon, C.F.; Martinez-Sanchez, M.V.; Gimeno, L.; Campillo, J.A.; Server-Pastor, G.; Martinez-Garcia, J.; Martinez-Escribano, J.; Torroba, A.; Ferri, B.; Abellan, D.J.; et al. Activating KIRs on Educated NK Cells Support Downregulation of CD226 and Inefficient Tumor Immunosurveillance. Cancer Immunol. Res. 2019, 7, 1307–1317. [Google Scholar] [CrossRef]
  47. Sanchez-Correa, B.; Gayoso, I.; Bergua, J.M.; Casado, J.G.; Morgado, S.; Solana, R.; Tarazona, R. Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol. Cell Biol. 2012, 90, 109–115. [Google Scholar] [CrossRef]
  48. Peng, Y.P.; Xi, C.H.; Zhu, Y.; Yin, L.D.; Wei, J.S.; Zhang, J.J.; Liu, X.C.; Guo, S.; Fu, Y.; Miao, Y. Altered expression of CD226 and CD96 on natural killer cells in patients with pancreatic cancer. Oncotarget 2016, 7, 66586–66594. [Google Scholar] [CrossRef]
  49. Rezaeifar, M.; Shahbaz, S.; Peters, A.C.; Gibson, S.B.; Elahi, S. Polyfunctional CD8(+)CD226(+)RUNX2(hi) effector T cells are diminished in advanced stages of chronic lymphocytic leukemia. Mol. Oncol. 2025, 19, 1347–1370. [Google Scholar] [CrossRef]
  50. Wang, X.; Mou, W.; Han, W.; Xi, Y.; Chen, X.; Zhang, H.; Qin, H.; Wang, H.; Ma, X.; Gui, J. Diminished cytolytic activity of gammadelta T cells with reduced DNAM-1 expression in neuroblastoma patients. Clin. Immunol. 2019, 203, 63–71. [Google Scholar] [CrossRef]
  51. Han, B.; Mao, F.Y.; Zhao, Y.L.; Lv, Y.P.; Teng, Y.S.; Duan, M.; Chen, W.; Cheng, P.; Wang, T.T.; Liang, Z.Y.; et al. Altered NKp30, NKp46, NKG2D, and DNAM-1 Expression on Circulating NK Cells Is Associated with Tumor Progression in Human Gastric Cancer. J. Immunol. Res. 2018, 2018, 6248590. [Google Scholar] [CrossRef]
  52. Ma, P.; Sun, W. Integrated single-cell and bulk sequencing analyses with experimental validation identify the prognostic and immunological implications of CD226 in pan-cancer. J. Cancer Res. Clin. Oncol. 2023, 149, 14597–14617. [Google Scholar] [CrossRef]
  53. Zhang, C.; Ding, Z.; Lv, G.; Li, J.; Zhang, J.F.; Zhou, P. CD226 rs727088A>G polymorphism increases the susceptibility to gastric cancer in Chinese populations. Gene 2015, 557, 92–97. [Google Scholar] [CrossRef] [PubMed]
  54. Qiu, Z.X.; Peng, Y.; Li, W.M. CD226 gene polymorphisms are associated with non-small-cell lung cancer in the Chinese Han population. Ther. Clin. Risk Manag. 2015, 11, 1259–1264. [Google Scholar] [CrossRef]
  55. Lee, J.H.; Yoo, S.S.; Hong, M.J.; Choi, J.E.; Kim, S.; Kang, H.G.; Do, S.K.; Kim, J.H.; Baek, S.A.; Lee, W.K.; et al. Impact of immune checkpoint gene CD155 Ala67Thr and CD226 Gly307Ser polymorphisms on small cell lung cancer clinical outcome. Sci. Rep. 2021, 11, 1794. [Google Scholar] [CrossRef] [PubMed]
  56. Worboys, J.D.; Vowell, K.N.; Hare, R.K.; Ambrose, A.R.; Bertuzzi, M.; Conner, M.A.; Patel, F.P.; Zammit, W.H.; Gali-Moya, J.; Hazime, K.S.; et al. TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation. Nat. Commun. 2023, 14, 5016. [Google Scholar] [CrossRef] [PubMed]
  57. Jin, H.S.; Ko, M.; Choi, D.S.; Kim, J.H.; Lee, D.H.; Kang, S.H.; Kim, I.; Lee, H.J.; Choi, E.K.; Kim, K.P.; et al. CD226(hi)CD8(+) T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy. Cancer Immunol. Res. 2020, 8, 912–925. [Google Scholar] [CrossRef]
  58. Fourcade, J.; Sun, Z.; Chauvin, J.M.; Ka, M.; Davar, D.; Pagliano, O.; Wang, H.; Saada, S.; Menna, C.; Amin, R.; et al. CD226 opposes TIGIT to disrupt Tregs in melanoma. JCI Insight 2018, 3, e121157. [Google Scholar] [CrossRef]
  59. Jin, Z.; Lan, T.; Zhao, Y.; Du, J.; Chen, J.; Lai, J.; Xu, L.; Chen, S.; Zhong, X.; Wu, X.; et al. Higher TIGIT(+)CD226(−) gammadelta T cells in Patients with Acute Myeloid Leukemia. Immunol. Investig. 2022, 51, 40–50. [Google Scholar] [CrossRef]
  60. Braun, M.; Aguilera, A.R.; Sundarrajan, A.; Corvino, D.; Stannard, K.; Krumeich, S.; Das, I.; Lima, L.G.; Meza Guzman, L.G.; Li, K.; et al. CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8(+) T Cells. Immunity 2020, 53, 805–823. [Google Scholar] [CrossRef]
  61. Mantovani, S.; Varchetta, S.; Mele, D.; Maiello, R.; Donadon, M.; Soldani, C.; Franceschini, B.; Torzilli, G.; Tartaglia, G.; Maestri, M.; et al. Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells. Cancers 2022, 14, 4060. [Google Scholar] [CrossRef] [PubMed]
  62. Guillerey, C.; Ferrari de Andrade, L.; Vuckovic, S.; Miles, K.; Ngiow, S.F.; Yong, M.C.; Teng, M.W.; Colonna, M.; Ritchie, D.S.; Chesi, M.; et al. Immunosurveillance and therapy of multiple myeloma are CD226 dependent. J. Clin. Investig. 2015, 125, 2077–2089. [Google Scholar] [CrossRef]
  63. Dastouri, M.; Kilic, N.; Yilmaz, H. The apoptotic effects of NK-92 cells stimulated with an anti-CD226 antibody on MDA-MB-231 triple-negative breast cancer cells. Med. Oncol. 2023, 40, 228. [Google Scholar] [CrossRef] [PubMed]
  64. Sayitoglu, E.C.; Georgoudaki, A.M.; Chrobok, M.; Ozkazanc, D.; Josey, B.J.; Arif, M.; Kusser, K.; Hartman, M.; Chinn, T.M.; Potens, R.; et al. Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D. Front. Immunol. 2020, 11, 40. [Google Scholar] [CrossRef] [PubMed]
  65. Li, Y.; Yang, F.; Sang, L.; Zhu, J.; Han, X.; Shan, F.; Li, S.; Zhai, J.; Wang, D.; Lu, C.; et al. Enhanced therapeutic effects against murine colon carcinoma induced by a Colon 26/Ag85A-CD226 tumor cell vaccine. Oncol. Rep. 2015, 34, 1795–1804. [Google Scholar] [CrossRef]
  66. Hou, S.; Zheng, X.; Wei, H.; Tian, Z.; Sun, R. Recombinant soluble CD226 protein directly inhibits cancer cell proliferation in vitro. Int. Immunopharmacol. 2014, 19, 119–126. [Google Scholar] [CrossRef]
  67. Takahashi, N.; Sugaya, M.; Suga, H.; Oka, T.; Kawaguchi, M.; Miyagaki, T.; Fujita, H.; Inozume, T.; Sato, S. Increased Soluble CD226 in Sera of Patients with Cutaneous T-Cell Lymphoma Mediates Cytotoxic Activity against Tumor Cells via CD155. J. Investig. Dermatol. 2017, 137, 1766–1773. [Google Scholar] [CrossRef]
  68. Di Pace, A.L.; Tumino, N.; Besi, F.; Alicata, C.; Conti, L.A.; Munari, E.; Maggi, E.; Vacca, P.; Moretta, L. Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor In Exosome-Mediated Cytotoxicity Against Tumor. Cancers 2020, 12, 661. [Google Scholar] [CrossRef]
  69. Tang, K.; Hou, Y.; Cheng, L.; Zhang, Y.; Li, J.; Qin, Q.; Zheng, X.; Jia, X.; Zhang, C.; Zhuang, R.; et al. Increased blood CD226(-) inflammatory monocytes with low antigen presenting potential correlate positively with severity of hemorrhagic fever with renal syndrome. Ann. Med. 2023, 55, 2247000. [Google Scholar] [CrossRef]
  70. Murillo, O.; Moreira, J.D.; Kujur, W.; Velasco-Alzate, K.; Sen Santara, S.; Konduru, N.V.; Mulik, S. Costimulatory CD226 Signaling Regulates Proliferation of Memory-like NK Cells in Healthy Individuals with Latent Mycobacterium tuberculosis Infection. Int. J. Mol. Sci. 2022, 23, 12838. [Google Scholar] [CrossRef]
  71. Qin, Y.; Chen, L.; Fei, Q.; Shao, X.; Lv, W.; Yang, J.; Xu, F.; Shi, J. Upregulation of CD226 on subsets of T cells and NK cells is associated with upregulated adhesion molecules and cytotoxic factors in patients with tuberculosis. Int. Immunopharmacol. 2023, 120, 110360. [Google Scholar] [CrossRef]
  72. Redlberger-Fritz, M.; Vietzen, H.; Puchhammer-Stockl, E. Association of Severe Influenza Virus Infections With CD226 (DNAM-1) Variants. J. Infect. Dis. 2019, 220, 1162–1165. [Google Scholar] [CrossRef] [PubMed]
  73. Tauriainen, J.; Scharf, L.; Frederiksen, J.; Naji, A.; Ljunggren, H.G.; Sonnerborg, A.; Lund, O.; Reyes-Teran, G.; Hecht, F.M.; Deeks, S.G.; et al. Perturbed CD8(+) T cell TIGIT/CD226/PVR axis despite early initiation of antiretroviral treatment in HIV infected individuals. Sci. Rep. 2017, 7, 40354. [Google Scholar] [CrossRef]
  74. Cella, M.; Presti, R.; Vermi, W.; Lavender, K.; Turnbull, E.; Ochsenbauer-Jambor, C.; Kappes, J.C.; Ferrari, G.; Kessels, L.; Williams, I.; et al. Loss of DNAM-1 contributes to CD8+ T-cell exhaustion in chronic HIV-1 infection. Eur. J. Immunol. 2010, 40, 949–954. [Google Scholar] [CrossRef]
  75. Nabekura, T.; Kanaya, M.; Shibuya, A.; Fu, G.; Gascoigne, N.R.; Lanier, L.L. Costimulatory molecule DNAM-1 is essential for optimal differentiation of memory natural killer cells during mouse cytomegalovirus infection. Immunity 2014, 40, 225–234. [Google Scholar] [CrossRef] [PubMed]
  76. Welch, M.J.; Teijaro, J.R.; Lewicki, H.A.; Colonna, M.; Oldstone, M.B. CD8 T cell defect of TNF-alpha and IL-2 in DNAM-1 deficient mice delays clearance in vivo of a persistent virus infection. Virology 2012, 429, 163–170. [Google Scholar] [CrossRef] [PubMed]
  77. Sakano, Y.; Sakano, K.; Hurrell, B.P.; Helou, D.G.; Shafiei-Jahani, P.; Kazemi, M.H.; Li, X.; Shen, S.; Hilser, J.R.; Hartiala, J.A.; et al. Blocking CD226 regulates type 2 innate lymphoid cell effector function and alleviates airway hyperreactivity. J. Allergy Clin. Immunol. 2024, 153, 1406–1422. [Google Scholar] [CrossRef]
  78. Zhang, Y.; Xie, Y.; Zhang, X.; Duan, C.; Ma, J.; Wang, Y.; Wu, Y.; Shan, N.; Cheng, K.; Zhuang, R.; et al. CD226 implicated in Akt-dependent apoptosis of CD4(+) T cell contributes to asthmatic pathogenesis. Cell Death Dis. 2024, 15, 705. [Google Scholar] [CrossRef]
  79. Xie, Y.; Zhang, Y.; Wang, T.; Liu, Y.; Ma, J.; Wu, S.; Duan, C.; Qiao, W.; Cheng, K.; Lu, L.; et al. Ablation of CD226 on CD4(+) T cells modulates asthma progress associated with altered IL-10 response and gut microbiota. Int. Immunopharmacol. 2023, 118, 110051. [Google Scholar] [CrossRef]
  80. Xie, Y.; Zhang, Y.; Zhu, T.; Ma, J.; Duan, C.; Yang, L.; Wang, T.; Zhuang, R.; Bian, K.; Lu, L. CD226 Deficiency Alleviates Murine Allergic Rhinitis by Suppressing Group 2 Innate Lymphoid Cell Responses. Mediat. Inflamm. 2022, 2022, 1756395. [Google Scholar] [CrossRef]
  81. Mosaad, Y.M.; El-Toraby, E.E.; Tawhid, Z.M.; Abdelsalam, A.I.; Enin, A.F.; Hasson, A.M.; Shafeek, G.M. Association between CD226 polymorphism and soluble levels in rheumatoid arthritis: Relationship with clinical activity. Immunol. Investig. 2018, 47, 264–278. [Google Scholar] [CrossRef]
  82. Du, Y.; Shen, L.X.; Yu, L.K.; Song, Y.; Zhu, J.F.; Du, R. The CD226 gene in susceptibility of rheumatoid arthritis in the Chinese Han population. Rheumatol. Int. 2012, 32, 1299–1304. [Google Scholar] [CrossRef] [PubMed]
  83. Hashemi, M.; Zakeri, Z.; Eskandari-Nasab, E.; Atabaki, M.; Pourhosseini, S.M.; Jahantigh, M.; Bahari, G.; Taheri, M. CD226 rs763361 (Gly307Ser) polymorphism is associated with susceptibility to rheumatoid arthritis in Zahedan, southeast Iran. Iran. Biomed. J. 2013, 17, 194–199. [Google Scholar] [PubMed]
  84. Tan, R.J.; Gibbons, L.J.; Potter, C.; Hyrich, K.L.; Morgan, A.W.; Wilson, A.G.; Isaacs, J.D.; Barton, A.; Braggss. Investigation of rheumatoid arthritis susceptibility genes identifies association of AFF3 and CD226 variants with response to anti-tumour necrosis factor treatment. Ann. Rheum. Dis. 2010, 69, 1029–1035. [Google Scholar] [CrossRef] [PubMed]
  85. Elhai, M.; Chiocchia, G.; Marchiol, C.; Lager, F.; Renault, G.; Colonna, M.; Bernhardt, G.; Allanore, Y.; Avouac, J. Targeting CD226/DNAX accessory molecule-1 (DNAM-1) in collagen-induced arthritis mouse models. J. Inflamm. 2015, 12, 9. [Google Scholar] [CrossRef] [PubMed]
  86. Nakano, M.; Ayano, M.; Kushimoto, K.; Kawano, S.; Higashioka, K.; Inokuchi, S.; Mitoma, H.; Kimoto, Y.; Akahoshi, M.; Ono, N.; et al. Association of elevated serum soluble CD226 levels with the disease activity and flares of systemic lupus erythematosus. Sci. Rep. 2021, 11, 16162. [Google Scholar] [CrossRef]
  87. Nakano, M.; Ayano, M.; Kushimoto, K.; Kawano, S.; Higashioka, K.; Inokuchi, S.; Mitoma, H.; Kimoto, Y.; Akahoshi, M.; Ono, N.; et al. Increased Proportion of CD226(+) B Cells Is Associated With the Disease Activity and Prognosis of Systemic Lupus Erythematosus. Front. Immunol. 2021, 12, 713225. [Google Scholar] [CrossRef]
  88. Du, Y.; Tian, L.; Shen, L.X.; Wang, F.; Yu, L.K.; Song, Y.; Zhu, J.F.; Du, R. Association of the CD226 single nucleotide polymorphism with systemic lupus erythematosus in the Chinese Han population. Tissue Antigens 2011, 77, 65–67. [Google Scholar] [CrossRef]
  89. Huang, Z.; Fu, B.; Zheng, S.G.; Li, X.; Sun, R.; Tian, Z.; Wei, H. Involvement of CD226+ NK cells in immunopathogenesis of systemic lupus erythematosus. J. Immunol. 2011, 186, 3421–3431. [Google Scholar] [CrossRef]
  90. Avouac, J.; Elhai, M.; Tomcik, M.; Ruiz, B.; Friese, M.; Piedavent, M.; Colonna, M.; Bernhardt, G.; Kahan, A.; Chiocchia, G.; et al. Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis. Ann. Rheum. Dis. 2013, 72, 1089–1098. [Google Scholar] [CrossRef]
  91. Ayano, M.; Tsukamoto, H.; Kohno, K.; Ueda, N.; Tanaka, A.; Mitoma, H.; Akahoshi, M.; Arinobu, Y.; Niiro, H.; Horiuchi, T.; et al. Increased CD226 Expression on CD8+ T Cells Is Associated with Upregulated Cytokine Production and Endothelial Cell Injury in Patients with Systemic Sclerosis. J. Immunol. 2015, 195, 892–900. [Google Scholar] [CrossRef] [PubMed]
  92. Dieude, P.; Guedj, M.; Truchetet, M.E.; Wipff, J.; Revillod, L.; Riemekasten, G.; Matucci-Cerinic, M.; Melchers, I.; Hachulla, E.; Airo, P.; et al. Association of the CD226 Ser(307) variant with systemic sclerosis: Evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis. Arthritis Rheum. 2011, 63, 1097–1105. [Google Scholar] [CrossRef]
  93. Abbasi, F.; Mansouri, R.; Gharibdoost, F.; Aslani, S.; Mostafaei, S.; Kavosi, H.; Poursani, S.; Sobhani, S.; Mahmoudi, M. Association Study of CD226 and CD247 Genes Single Nucleotide Polymorphisms in Iranian Patients with Systemic Sclerosis. Iran. J. Allergy Asthma Immunol. 2017, 16, 471–479. [Google Scholar]
  94. Deng, C.; Chen, Y.; Li, W.; Peng, L.; Luo, X.; Peng, Y.; Zhao, L.; Wu, Q.; Zhang, W.; Zhang, X.; et al. Alteration of CD226/TIGIT immune checkpoint on T cells in the pathogenesis of primary Sjogren’s syndrome. J. Autoimmun. 2020, 113, 102485. [Google Scholar] [CrossRef] [PubMed]
  95. Zhao, P.; Cheng, W.; Liu, C.; Peng, C.; Shen, Y.; Yang, Y.; Sun, C.; Chang, X.; Wu, J. Increased proportion of CD226 + CD14 + monocytes correlates with clinical features and laboratory parameters in patients with primary Sjogren’s syndrome. Int. J. Rheum. Dis. 2023, 26, 2460–2469. [Google Scholar] [CrossRef] [PubMed]
  96. Ding, S.; Zhao, P.; Song, S.; Yang, Y.; Peng, C.; Chang, X.; Liu, C. A novel enzyme-linked immunosorbent assay tool to evaluate plasma soluble CD226 in primary Sjogren’s syndrome. Anal. Biochem. 2024, 692, 115573. [Google Scholar] [CrossRef]
  97. Xi, J.S.; Nie, C.L.; Wang, J.; Ma, Y.; Ma, A.H. Association of CD226 polymorphisms with the susceptibility to type 1 diabetes in Chinese children. Genet. Mol. Res. 2015, 14, 15249–15255. [Google Scholar] [CrossRef]
  98. Mattana, T.C.; Santos, A.S.; Fukui, R.T.; Mainardi-Novo, D.T.; Costa, V.S.; Santos, R.F.; Matioli, S.R.; da Silva, M.E. CD226 rs763361 is associated with the susceptibility to type 1 diabetes and greater frequency of GAD65 autoantibody in a Brazilian cohort. Mediat. Inflamm. 2014, 2014, 694948. [Google Scholar] [CrossRef]
  99. Shapiro, M.R.; Yeh, W.I.; Longfield, J.R.; Gallagher, J.; Infante, C.M.; Wellford, S.; Posgai, A.L.; Atkinson, M.A.; Campbell-Thompson, M.; Lieberman, S.M.; et al. CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation. Front. Immunol. 2020, 11, 2180. [Google Scholar] [CrossRef]
  100. Brown, M.E.; Thirawatananond, P.; Peters, L.D.; Kern, E.J.; Vijay, S.; Sachs, L.K.; Posgai, A.L.; Brusko, M.A.; Shapiro, M.R.; Mathews, C.E.; et al. Inhibition of CD226 co-stimulation suppresses diabetes development in the NOD mouse by augmenting regulatory T cells and diminishing effector T cell function. Diabetologia 2025, 68, 397–418. [Google Scholar] [CrossRef]
  101. Zhong, T.; Li, X.; Lei, K.; Tang, R.; Deng, Q.; Love, P.E.; Zhou, Z.; Zhao, B.; Li, X. TGF-beta-mediated crosstalk between TIGIT(+) Tregs and CD226(+)CD8(+) T cells in the progression and remission of type 1 diabetes. Nat. Commun. 2024, 15, 8894. [Google Scholar] [CrossRef] [PubMed]
  102. Kari, S.; Bucciarelli, F.; Angles, T.; Oster, A.C.; Cauboue, P.; Laviolette, K.; Mougenot, M.; Morandi, E.; Bernard, I.; Pignolet, B.; et al. Increased levels of circulating soluble CD226 in multiple sclerosis. Mult. Scler. 2024, 30, 654–663. [Google Scholar] [CrossRef] [PubMed]
  103. Wang, N.; Liang, S.; Jin, J.; Fang, L.; Ma, Q.; Wang, X.; Song, Y.; Chen, L. CD226 attenuates Treg suppressive capacity via CTLA-4 and TIGIT during EAE. Immunol. Res. 2019, 67, 486–496. [Google Scholar] [CrossRef] [PubMed]
  104. Wang, N.; Yi, H.; Fang, L.; Jin, J.; Ma, Q.; Shen, Y.; Li, J.; Liang, S.; Xiong, J.; Li, Z.; et al. CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model. Front. Immunol. 2020, 11, 1883. [Google Scholar] [CrossRef]
  105. Zhang, R.; Zeng, H.; Zhang, Y.; Chen, K.; Zhang, C.; Song, C.; Fang, L.; Xu, Z.; Yang, K.; Jin, B.; et al. CD226 ligation protects against EAE by promoting IL-10 expression via regulation of CD4+ T cell differentiation. Oncotarget 2016, 7, 19251–19264. [Google Scholar] [CrossRef]
  106. Chen, P.; Wu, M.; Wang, N.; Xia, F.; Du, F.; Liu, Z.; Wang, J.; Jin, J.; Jin, B.; Zhao, G.; et al. Expression of CD226 is upregulated on Tr1 cells from neuromyelitis optica spectrum disorder patients. Brain Behav. 2022, 12, e2623. [Google Scholar] [CrossRef]
  107. Liu, C.; Wang, G.; Liu, H.; Li, Y.; Li, J.; Dai, Y.; Hu, X. CD226 Gly307Ser association with neuromyelitis optica in Southern Han Chinese. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 2012, 39, 488–490. [Google Scholar] [CrossRef]
  108. Capozzi, A.; Manganelli, V.; Riitano, G.; Caissutti, D.; Longo, A.; Garofalo, T.; Sorice, M.; Misasi, R. Advances in the Pathophysiology of Thrombosis in Antiphospholipid Syndrome: Molecular Mechanisms and Signaling through Lipid Rafts. J. Clin. Med. 2023, 12, 891. [Google Scholar] [CrossRef]
  109. Riitano, G.; Capozzi, A.; Recalchi, S.; Caissutti, D.; Longo, A.; Mattei, V.; Conti, F.; Misasi, R.; Garofalo, T.; Sorice, M.; et al. Anti-beta2-GPI Antibodies Induce Endothelial Cell Expression of Tissue Factor by LRP6 Signal Transduction Pathway Involving Lipid Rafts. Cells 2022, 11, 1288. [Google Scholar] [CrossRef]
  110. Shirakawa, J.; Wang, Y.; Tahara-Hanaoka, S.; Honda, S.; Shibuya, K.; Shibuya, A. LFA-1-dependent lipid raft recruitment of DNAM-1 (CD226) in CD4+ T cell. Int. Immunol. 2006, 18, 951–957. [Google Scholar] [CrossRef]
  111. Long, Y.; Lu, K.J.; Xia, C.S.; Feng, J.H.; Li, W.Y.; Ma, Y.T.; Sun, Y.Y.; Fan, C.H.; Li, C. Altered CD226/TIGIT expressions were associated with NK phenotypes in primary antiphospholipid syndrome and affected by IL-4/JAK pathway. Clin. Exp. Immunol. 2024, 216, 132–145. [Google Scholar] [CrossRef] [PubMed]
  112. Reinards, T.H.; Albers, H.M.; Brinkman, D.M.; Kamphuis, S.S.; van Rossum, M.A.; Girschick, H.J.; Wouters, C.; Hoppenreijs, E.P.; Saurenmann, R.K.; Hinks, A.; et al. CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis. Ann. Rheum. Dis. 2015, 74, 2193–2198. [Google Scholar] [CrossRef] [PubMed]
  113. Li, W.; Deng, C.; Yang, H.; Tian, X.; Chen, L.; Liu, Q.; Gao, C.; Lu, X.; Wang, G.; Peng, Q. Upregulation of the CD155-CD226 Axis Is Associated With Muscle Inflammation and Disease Severity in Idiopathic Inflammatory Myopathies. Neurol. R Neuroimmunol. Neuroinflamm. 2023, 10, e200143. [Google Scholar] [CrossRef] [PubMed]
  114. Hafler, J.P.; Maier, L.M.; Cooper, J.D.; Plagnol, V.; Hinks, A.; Simmonds, M.J.; Stevens, H.E.; Walker, N.M.; Healy, B.; Howson, J.M.; et al. CD226 Gly307Ser association with multiple autoimmune diseases. Genes Immun. 2009, 10, 5–10. [Google Scholar] [CrossRef]
  115. Qiu, Z.X.; Zhang, K.; Qiu, X.S.; Zhou, M.; Li, W.M. CD226 Gly307Ser association with multiple autoimmune diseases: A meta-analysis. Hum. Immunol. 2013, 74, 249–255. [Google Scholar] [CrossRef]
Biomolecules 15 01007 g001
Figure 1. Interactions of CD226 and TIGIT with shared ligands. CD226 and TIGIT are immunoregulatory receptors, primarily expressed on T cells and NK cells, that interact with shared ligands CD112 and CD155. These ligands are often displayed on antigen-presenting cells and transformed cells. Upon ligand binding, CD226 mediates activating signals via its immunoglobulin tyrosine tail (ITT)/ITT-like motif, whereas TIGIT delivers inhibitory signals through ITIM and ITT-like motifs.
Figure 1. Interactions of CD226 and TIGIT with shared ligands. CD226 and TIGIT are immunoregulatory receptors, primarily expressed on T cells and NK cells, that interact with shared ligands CD112 and CD155. These ligands are often displayed on antigen-presenting cells and transformed cells. Upon ligand binding, CD226 mediates activating signals via its immunoglobulin tyrosine tail (ITT)/ITT-like motif, whereas TIGIT delivers inhibitory signals through ITIM and ITT-like motifs.
Biomolecules 15 01007 g001
Table 1. Effects of CD226 in immune cells.
Table 1. Effects of CD226 in immune cells.
Cell TypeRoles of CD226
Conventional T cells Enhances CD8+ T cell maturation and memory formation [16,17]; promotes Th1/Th17 polarization via enhanced IL-17/IFN-γ production [18,19]; facilitates early Tfh differentiation and proliferation [21]
Treg cellsDual roles: impairs stability/suppressive function [24,25] vs. maintains metabolic fitness/lineage stability [26]
NK cellsEnhances activation, cytotoxicity and stable target cell interactions [30,31]; modulates NK cell education [34]
MacrophagesDrives M1 polarization [37,38,39]
Table 2. The roles of CD226 in immune-mediated disorders.
Table 2. The roles of CD226 in immune-mediated disorders.
Disease CategoryDisease/ContextRoles of CD226
Tumor Multiple Tumor TypesHigh CD226+ TILs infiltration correlate with better prognosis [41,42,43,44,45,46,47,48,49,50,51]; tumor-induced CD226 downregulation promotes immune evasion [60,61]; polymorphisms increase cancer susceptibility and influence treatment response [53,54,55]
Infectious DiseasesViral Infections Reduced expression on immune cells impairs antiviral immunity [69,73,74,75,76]
               TuberculosisElevated expression on NK/T cells enhances effector functions [70,71]
Allergic DiseasesAsthmaUpregulation in Th2/Th17/ILC2s drives inflammation [77,78]
               Allergic RhinitisDeficiency reduces Th2 cytokines, eosinophil recruitment, and inflammatory responses [80]
Autoimmune DiseasesRheumatoid Arthritisrs763361 polymorphism confers susceptibility [81,82,83]; soluble CD226 correlates with disease activity [81]
 Systemic Lupus ErythematosusIncreased soluble CD226 and CD226+ switched-memory B cells correlate with disease activity [86,87]; rs763361 polymorphism increases susceptibility [88]
 Systemic SclerosisOverexpression in skin tissue/CD8+ T cells drives pro-inflammatory cytokines secretion [90,91]; rs763361 T allele is genetic risk in Europeans [92]
 Primary Sjögren’s SyndromeIncreased proportions of CD226+ CD4+ T cells/monocytes correlate with disease severity [94,95]; reduced soluble CD226 inversely associates with disease progression [96]
 Type 1 Diabetesrs763361 polymorphism increases susceptibility [97,98]; blockade delays insulitis onset [99,100,101]
 Multiple Sclerosis and Neuromyelitis OpticaIncreased soluble CD226 correlates with neuroinflammation [102]; CD226 deficiency attenuates experimental autoimmune encephalomyelitis severity [103,104,105]
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Liu, K.; Liu, Y.; Xiong, H.; Ning, Z. The Immune Regulatory Functions of CD226 and Its Implications in Immune-Mediated Diseases. Biomolecules 2025, 15, 1007. https://doi.org/10.3390/biom15071007

AMA Style

Liu K, Liu Y, Xiong H, Ning Z. The Immune Regulatory Functions of CD226 and Its Implications in Immune-Mediated Diseases. Biomolecules. 2025; 15(7):1007. https://doi.org/10.3390/biom15071007

Chicago/Turabian Style

Liu, Keyan, Yuanzhen Liu, Huabao Xiong, and Zhaochen Ning. 2025. "The Immune Regulatory Functions of CD226 and Its Implications in Immune-Mediated Diseases" Biomolecules 15, no. 7: 1007. https://doi.org/10.3390/biom15071007

APA Style

Liu, K., Liu, Y., Xiong, H., & Ning, Z. (2025). The Immune Regulatory Functions of CD226 and Its Implications in Immune-Mediated Diseases. Biomolecules, 15(7), 1007. https://doi.org/10.3390/biom15071007

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