Search Results (233)

Background/Objectives: Chronic pain is a significant clinical challenge, in part due to the absence of reliable objective biomarkers for its evaluation and treatment. Growing evidence indicates that immune cells, including natural killer (NK) cells, are involved in the regulation of pain processes. NK cells are innate cytotoxic lymphocytes whose functional status may mirror underlying pathological pain states. In this study, we investigated μ-opioid receptor (MOR) expression and functional alterations of NK cells in a murine model of neuropathic pain induced by chronic constriction injury (CCI). Methods: Mice were divided into three groups: Sham (sciatic nerve exposure without ligation), CCI 14-day, and CCI 21-day groups. At the respective time points, animals were sacrificed and spleens were collected for analysis. Splenocytes were isolated by mechanical dissociation followed by centrifugation and erythrocyte lysis. Lymphocytes were analyzed by flow cytometry to evaluate MOR expression in NK cells and their degranulation activity (CD107a assay). Cells were incubated with fluorochrome-conjugated antibodies against NK cell markers (NK1.1, CD3, Ly49A, Ly49C/I) in combination with anti-MOR and anti-Interferon γ antibody (IFN-γ). Immunofluorescence and confocal microscopy analyses were performed to assess MOR localization and granzyme localization, supporting CD107a-mediated degranulation. Results: Flow cytometry analysis revealed a significant reduction in surface MOR expression on total NK cells from CCI mice compared with sham controls at 14 and 21 days post-injury, a finding corroborated by immunofluorescence evidence of MOR cellular internalization. Functionally, CCI induced a marked decrease in CD107a expression and impaired IFN-γ production both under basal conditions and following PMA/ionomycin stimulation, indicating a hyporesponsive state of NK cells. Consistently, confocal microscopy revealed extracellular release of Granzyme A following CCI, suggesting dysregulated degranulation. Conclusions: Neuropathic pain is associated with a remodeling of NK cell phenotype and effector functions, characterized by impaired cytotoxic activity and cytokine production, along with modulation of inhibitory receptor expression. Notably, MOR-reduced surface expression in NK cells emerges as a potential biomarker of neuropathic pain. Further studies are needed to elucidate the molecular mechanisms regulating MOR expression and its relationship with NK cell hyporesponsiveness and degranulation in chronic pain conditions. Full article

(1) Background: Innate lymphoid cells (ILCs) are potent cytokine producers that regulate local immune responses in tissues. Natural killer (NK) cells belong to group 1 ILCs and play an important role in tumor clearance and defense against intracellular pathogens. ILC2 and 3 have been implied in allergic responses and other chronic inflammatory diseases. The role of these cells in the pathogenesis of chronic rhinosinusitis (CRS) is not completely understood. There are changes in the cellular infiltrate in the mucosa of patients with CRS with and without polyps. The aim of this study was to characterize the number and phenotype of NK cells, ILC2s and ILC3s in patients with CRS. (2) Methods: Tissue samples were collected from patients with CRS with and without nasal polyps who were undergoing nasal sinus surgery as well as control patients who were undergoing surgery due to non-inflammatory reasons. Lymphocytes were isolated from the tissues using mechanical and enzymatic dissociation. Peripheral blood lymphocytes were obtained from the same patients. All cells were examined by multicolor flow cytometry. NK cells were analyzed for the distribution of CD56^dimCD16⁺ and CD56^brightCD16⁻ subsets and the expression of IL18Rα, CD16, CD57, GATA3, TCF1 and NKp44. In ILC2s, GATA3 and IL18Rα expression was determined, and ILC3s as well as NKp44⁺ and NKp44⁻ILC3 subsets were analyzed for the expression of IL18Rα. (3) Results: There were significantly fewer NK cells in the nasal polyps compared to the peripheral blood of patients with CRSwNP and tissues from CRSsNP patients, which both showed higher levels of TCF1 expression. Irrespective of the disease condition, NK cells in tissues showed lower CD16 expression and a lower frequency of the CD56^dimCD16⁺ subset compared to the peripheral blood mononuclear cells. Additionally, a smaller percentage of NK cells were terminally matured, as measured by CD16⁺ and CD57⁺ expression, in all examined nasal mucosa tissues. In the tissue ILC3s, we predominantly found cells from the NKp44⁻ subset in all groups. ILC3s from CRSsNP patients showed the highest frequencies of IL18Rα⁺ cells of all examined tissues. ILC2s from the polyps ofCRSwNP patients showed higher levels of GATA3 expression than their peripheral blood counterparts. (4) Conclusions: We found that tissue-resident NK cells in mucosa from the nose and sinuses are a more heterogenous and less mature population than those in peripheral blood. Expression of the examined markers in NK cells was similar among groups. NK cell frequency, both in blood and tissue from CRSsNP patients, was higher than in the other groups, indicating that these cells might play an important role in this phenotype. Changes in the IL18Rα expression of ILC3s suggest a potential role of IL18 signaling in CRS pathogenesis. Full article

FcγRIII (CD16) is expressed by several leukocyte populations, including monocytes, macrophages, and natural killer cells, and plays an important role in IgG-mediated immune responses. Altered CD16 expression has been reported in inflammatory and autoimmune conditions, including thyroid-associated immune alterations. This preliminary in vitro study investigated whether the indole-derived compounds melatonin and indole-3-propionic acid (IPA) affect surface FcγRIII/CD16-related parameters in porcine peripheral blood mononuclear cells (PBMCs) cultured alone or with autologous thyroid follicular cells. PBMCs were left untreated or treated with melatonin or IPA, both at 50 µM, and analysed by flow cytometry at baseline and after 24 and 48 h of culture. The percentage of CD45⁺CD16⁺ cells and the CD16 mean fluorescence intensity were assessed as surface CD16-related parameters. Untreated PBMC cultures showed a time-dependent decrease in both the percentage of CD45⁺CD16⁺ cells and CD16 mean fluorescence intensity. Melatonin and IPA further enhanced this decrease compared with untreated cultures. Co-culture with thyroid follicular cells did not significantly modify CD16-related parameters under the tested conditions. These findings suggest that melatonin and IPA may modulate the surface CD16-related phenotype of porcine CD45⁺ leukocytes in vitro. The results provide preliminary evidence for the potential immunomodulatory activity of indole-derived compounds within the CD16-expressing leukocyte compartment and warrant further investigation in extended experimental models. Full article

Endometriosis (EM) and chronic endometritis (CE) are both implicated in female infertility, yet the relationship between them remains incompletely understood. In this narrative review, we synthesize non-systematically selected clinical and mechanistic evidence on EM–CE coexistence, with emphasis on infertility-related settings and diagnostic uncertainty. Available studies, largely from selected infertility cohorts, suggest that CE is identified more often in women with EM, raising the possibility that their coexistence reflects a biologically meaningful association rather than incidental overlap. The two conditions share several abnormalities that may impair reproduction, including persistent inflammation, immune dysregulation, altered cytokine and chemokine signaling, impaired macrophage and natural killer cell function, progesterone resistance, and reduced endometrial receptivity. In addition to the pelvic anatomical distortion and ovarian dysfunction associated with EM, CE may further compromise implantation by impairing decidualization, displacing the window of implantation, and disrupting the local endometrial microenvironment. Both conditions also remain diagnostically challenging. EM is most reliably confirmed by laparoscopy with histologic verification, whereas CE is generally diagnosed by hysteroscopy and endometrial biopsy demonstrating plasma cells. For CE in particular, the lack of standardized diagnostic criteria and uniform CD138 thresholds continues to limit diagnostic consistency. Emerging imaging techniques, molecular biomarkers, microbiota-based approaches, and artificial intelligence-assisted models remain investigational or adjunctive rather than established tools for routine integrated assessment. Taken together, the current evidence is hypothesis-generating and supports selective, phenotype-driven consideration of coexisting EM and CE in infertility care rather than routine dual invasive evaluation. Further studies are required to clarify the mechanisms linking these conditions, define their combined reproductive impact, and determine whether integrated diagnostic and therapeutic strategies can improve fertility outcomes. Full article

Kidney transplantation remains the optimal treatment for end-stage renal disease, yet long-term allograft survival has plateaued due to persistent rejection. This review provides a comprehensive overview of the inflammatory and immune pathways implicated in kidney allograft rejection, integrating current evidence from basic and translational research. Ischemia–reperfusion injury initiates an inflammatory cascade through the release of damage-associated molecular patterns, activating Toll-like receptors and the complement system, thereby priming the alloimmune response. Innate immune cells, including macrophages, dendritic cells, and natural killer cells, bridge sterile tissue injury to adaptive alloimmunity, while the emerging concept of trained immunity reveals long-lasting epigenetic reprogramming of monocytes with direct implications for graft longevity. The adaptive response encompasses T cell-mediated rejection, driven by Th1, Th17, and CD8⁺ cytotoxic lymphocytes, and antibody-mediated rejection, mediated by donor-specific antibodies through complement activation and antibody-dependent cellular cytotoxicity. Key signalling pathways, including JAK-STAT, NF-κB, NLRP3 inflammasome, and mTOR, amplify allograft inflammation and promote progression toward chronic injury. Macrophage polarisation and macrophage-to-myofibroblast transition have been identified as major drivers of interstitial fibrosis and late graft failure. Recent advances in non-invasive biomarkers, such as donor-derived cell-free DNA and molecular phenotyping, are transforming rejection diagnostics. Emerging therapies, including costimulation blockade, anti-CD38 antibodies, complement inhibitors, and regulatory T cell-based approaches, offer the potential to shift transplant medicine toward precision-guided, tolerance-inducing strategies. This review synthesises these developments and discusses future perspectives for improving long-term allograft outcomes. Full article

Background: Colorectal cancer is a common malignancy and 5-fluorouracil (FU) remains a mainstay of chemotherapy despite its toxicity. As an important part of comprehensive tumor treatment, dual-protein (DP) nutritional intervention is attracting more and more attention. Methods: This study preliminarily evaluated the regulatory effects of DP intervention on colorectal cells of CT26 tumor-bearing mice, examining the dosage and administration methods of DP, as well as the anti-tumor effects of FU alone or in combination with DP. Results: The results showed that low- and medium-dose DP numerically increased spleen index and showed trends toward alleviating FU-induced thymic atrophy, splenic damage, nephrotoxicity, and myocardial injury. It also partly mitigated muscle wasting, prevented FU-induced shortening of the colorectal tract, and reduced intestinal injury. In addition, DP was associated with increased lymphocyte, monocyte, and platelet counts and decreased granulocytes, suggesting possible alleviation of chemotherapy-induced bone marrow suppression and a potential effect on hematopoietic function. Flow cytometry results indicated possible effects of DP on CD4⁺ T and CD8⁺ T cell proliferation or apoptosis, modulation of effector and memory phenotypes, reduced splenic neutrophil levels, balanced B cell function, and maintained natural killer cell activity. In addition, DP intervention also showed trends toward regulating hepatic lipid metabolism and partially alleviating FU-induced dyslipidemia and muscle damage. In addition, DP and FU could increase IL-2, IL-10, GM-CSF and IFN-γ and decrease IL-6 and TNF-α. Conclusions: In conclusion, a moderate dose (0.67 g/kg) of DP had the most favorable trends, and the pre-intervention mode was more effective. This study also provided exploratory data on the potential of DP in reducing chemotherapy-related toxicity. These findings will provide preliminary scientific support for nutritional therapy in colorectal cancer patients, as well as for the research, development, and application of dual-protein foods for special medical purposes. Full article

This study is a narrative review of natural killer (NK) cells in Behcet disease (BD). BD is an inflammatory disorder with manifestations in mucosal tissues. Unlike autoimmune diseases that generate autoantibodies, BD is believed to be an autoinflammatory disease triggered by innate immune cells rather than adaptive cells. Hyperactivation of neutrophils causes vasculitis and thrombosis, and they migrate into cutaneous and ocular lesions. Dominance of M1 macrophages promotes the differentiation of Th1 cells. Moreover, the cross-reaction of bacterial heat shock proteins induces production of cytokines such as IL-4 and IFN-γ in γδT cells, which alters the balance between Th1 and Th2 phenotypes. Nevertheless, NK cells play more critical roles in BD pathogenesis than other innate immune cells because not only is their activity precisely controlled by the interaction between ligands and receptors, but NK1 shift also elicits Th1 dominance. The genetic factors associated with BD are HLA-B51 and major histocompatibility complex class I-related chain A (MICA), which stimulate NK receptors as ligands. Improperly processed peptides dysregulate their interaction with NK receptors, triggering the inflammatory response. NK1 and NK2 subsets represent cytokine production in relapse and remission periods; however, the cytotoxicity of NK cells in relapse is lower than that in remission periods. It still remains unclear how NK cells are activated recurrently and expand cytokine production. This review highlights the regulation of gene expression encoding NK receptors, tissue-resident NK cells, and adaptive NK cells to discuss their potential for relapse. Splicing variants and readthrough genes encoding NK receptors easily alter cytokine production. Moreover, tissue-resident NK cells in mucosal tissues and adaptive NK cells that memorize the virus infection have the potential to trigger hyperactivation in relapse. Full article

New anticancer therapeutic strategies, including targeting of iron dysregulation in affected cancer types and stages, are urgently needed to decrease the associated annual cancer death rate of about 10 million worldwide. Many tumours evade treatment and support metastatic potential by effluxing iron and upregulating antioxidant systems, leading to suppression of lipid peroxidation and ferroptotic cell death. Similarly, many tumours manipulate the tumour microenvironment (TME) by ensuring the continuous supply of iron. This involves phenotypic modulation of immune cells, including macrophages, neutrophils, regulatory T lymphocytes, and natural killer cells, as well as fibroblasts, contributing to immune evasion and tumour growth. In particular, tumour-associated macrophages (TAMs), which may account for about half of the tumour’s bulk, become progressively heavily loaded with iron and can be detected by magnetic resonance imaging (MRI) technologies. Clinically effective iron chelation therapy protocols in iron-overloaded conditions using the chelating drugs deferoxamine, deferasirox, and especially deferiprone can also potentially remove excess iron from TAMs and may decrease tumour malignancy. Deferiprone can also remove excess iron from iron-loaded renal cancer cells and potentially prevent metastasis in renal carcinoma. The anticancer potential of deferiprone has also been shown in other cancers, including iron removal in prostate cancer and through cancer stem cell inhibition in breast cancer. Many ongoing clinical trials using different drugs and experimental agents for inducing or modulating ferroptosis also support the translational potential of ferroptosis-based therapeutic strategies in selected categories of cancer patients. These advances highlight ferroptosis as a potential key metabolic vulnerability with relevance for treatment-resistant and metastatic tumours. Overall, iron chelation therapeutic approaches and ferroptosis-targeting may be considered for significant use as monotherapies or in combination with other anticancer drugs and could potentially improve therapeutic outcomes and limit disease progression and mortality in many cancers. Full article

Pancreatic ductal adenocarcinoma (PDAC) has high mortality rates, poor prognosis, and currently limited effective treatments. Natural killer (NK) cells from tumor-infiltrating lymphocytes (TIL) show promise for cancer treatment due to their ability to migrate to the tumor microenvironment (TME) and safe profile. However, expanding functional patient-derived NK cells remains challenging. Here, we cultured, expanded, and characterized TIL-NK cells isolated from central and peripheral tumor regions from PDAC. Ex vivo patient-derived PBMCs and TIL were cultured under IL-2, IL-15, and IL-12 stimulation. Phenotypical and functional NK cell characterization was assessed at the time of surgery and after 12 days of culture evaluating immunophenotype, expansion rate, and activation. A distinct distribution of NK cell infiltration was observed within the TME, with higher NK cell numbers in the periphery of the tumor compared to the central area. Most NK cells displayed a cytotoxic phenotype (CD56⁺ CD16⁺). Compared to PBMCs, TIL-NK cells expressed lower activation markers but superior tumor infiltration and expansion rates, particularly those isolated from the central regions. Notably, cytokine stimulation improved patient-derived NK cell activation and cytotoxic profile. This pilot study provides preliminary but critical insights regarding TIL-NK cells from PDAC patients, laying groundwork for developing NK cell-based immunotherapies for solid tumors. Full article

Background/Objectives: Oral squamous cell carcinoma (OSCC) is a tumor characterized by heterogeneous clinical behavior and prognosis. The tumor immune microenvironment plays a significant role in tumor progression and patient prognosis. p16 expression has been investigated as a surrogate biomarker in certain subtypes of head and neck squamous cell carcinomas, but its prognostic significance in oral squamous cell carcinoma remains incompletely elucidated. Methods: A retrospective cohort of 59 patients diagnosed with primary oral squamous cell carcinoma was analyzed. Tumor samples were evaluated for p16 expression and immunohistochemical markers associated with immune cell populations. Associations between immune microenvironment features, p16 status, and clinical outcomes such as recurrence and survival rate were analyzed. Results: p16-positive tumors were predominantly associated with immunotype A and exhibited higher densities of CD8+ cytotoxic T lymphocytes and natural killer (NK) cells. In contrast, immunotype B tumors showed similar characteristics regardless of p16 status, with no significant differences between p16-positive and p16-negative cases. Distinct immune profiles were variably associated with clinicopathological features and patient outcomes. Conclusions: These findings suggest that the immunological phenotype of oral squamous cell carcinoma may represent a potential prognostic factor. Full article

Natural killer (NK) cells are effector cells of the innate immune system. The cytokine microenvironment influences NK cell function. Dysregulation of NK cell cytotoxicity can manifest in reproductive disorders and is also observed in tumor-transformed tissues. The search for immunotherapies capable of regulating NK cell activity is therefore relevant. This study aimed to evaluate the effect of the TGFβ signaling pathway inhibitor and the cyclin-dependent kinase (CDK) 7/12/13 inhibitor on the transcriptional profile of NK-92 cell line. In the study, the cytokines TGFβ1, IL-12, IL-15, IL-18, and TNFα, and the TGFβ receptor type 1 (TGFβR1) inhibitor LY3200882 and the CDK7/12/13 inhibitor THZ1 were used. The cells were cultured sequentially in the presence of inhibitors and cytokines, followed by assessment of the gene expression of NCR2, NCR3, AHR, NCAM1, B3GAT1, EOMES, GATA3, KLRC1, KLRC2, CCL5, IL10 and TBX21. We observed direct effects of the inhibitors on NK cells. LY3200882 increased the expression of KLRC1 and B3GAT1, and reduced NCAM1. THZ1 increased the expression of KLRC1, KLRC2, AHR and EOMES, while it reduced IL-10 and NCR2. IL-12, IL-15, IL-18, and TNFα modified the gene expression of some phenotypic and cytotoxic receptors and transcription factors. TGFβ1 increased the expression of KLRC1, NCAM1, and B3GAT1. Blocking TGFβ-dependent signaling with LY3200882 abolished TGFβ1 effects. We assessed CD56 presence on NK-92 cell membrane and found its increase in the presence of LY3200882. After LY3200882 treatment, in the presence of TGFβ1 and choriocarcinoma cell line JEG-3, the expression of CD56 receptor on NK cell membrane decreased. Pretreating NK cells with THZ1 decreased the expression of NCAM1, B3GAT1, and EOMES in the presence of TGFβ1. Thus, LY3200882 partially neutralized TGFβ1 effects on the expression of NK cell receptor genes. THZ1 followed by TGFβ1 treatment promoted NK cell transcriptional profile characteristic for CD56dim NK cells. Both LY3200882 and THZ1 affected the NK cell transcription even without cytokine treatment. The independent effects of synthetic inhibitors on NK cells, as well as their influence in the presence of tumor cells, should be considered. Full article

Background: Renal allograft rejection remains a major challenge in transplantation. Current diagnostic approaches, including biopsies, are invasive and may fail to detect subclinical immune activation, potentially contributing to progressive graft dysfunction. Reliable, non-invasive biomarkers capable of monitoring immune activation and distinguishing rejection phenotypes are therefore needed. Methods: In this retrospective study, we evaluated serum neopterin as a biomarker of immune activation and graft status over 12 months following transplantation. Associations between neopterin levels and immune parameters, including natural killer (NK)-to-CD3⁺CD16/CD56⁺ T cell ratios, cytokines (IFN-γ and IL-10), and CD4⁺CD25⁺FoxP3⁺ T cell frequencies, were assessed. A total of 211 first renal allograft recipients were followed longitudinally, including patients with acute rejection (AR) and matched stable graft (SG) recipients. Serum neopterin was quantified by enzyme immunoassay, and immunophenotyping, mRNA expression, and cytokine profiling were performed on peripheral blood samples. Results: Serum neopterin levels were significantly elevated in AR compared to SG recipients, with a threshold of 57 nmol/L distinguishing AR with 81% sensitivity and 80% specificity. While IFN-γ demonstrated higher diagnostic performance in cross-sectional analysis, neopterin showed a more sustained elevation over time, remaining increased in AR recipients even at later post-transplant time points. Neopterin correlated positively with IFN-γ, but not IL-10, and inversely with CD4⁺CD25⁺FoxP3⁺ T cell frequency. NK cells were enriched during rejection, whereas CD3⁺CD16/CD56⁺ T cells were more prominent in graft stability. The NK-to-CD3⁺CD16/CD56⁺ T cell ratio was highest during acute cellular rejection. Conclusions: Neopterin reflects Th1-associated immune activation in renal allograft recipients and provides a temporally stable, non-invasive marker of immune status. Although it does not outperform IFN-γ levels at the time of rejection, its stability and sustained elevation suggest a complementary role in longitudinal monitoring. Integration of neopterin with immune parameters, including cytokine profiles and cellular subsets, may enhance the assessment of graft immunological status and support clinical decision-making. Full article

Natural killer (NK) cells, key effectors of innate immunity, are classically categorized into CD56^dim and CD56^bright subsets in humans. While murine NK cell heterogeneity has become increasingly recognized, the classification of mature NK cell subsets remains incompletely defined. Here, we comprehensively characterized CD127⁺ NK cells in mice and identified them as a distinct, mature subset, developing independently of the thymus and interleukin (IL)-15 signaling. Flow cytometric analyses revealed that CD127⁺ NK cells are broadly distributed across lymphoid and non-lymphoid tissues—including in C57BL/6 wild-type and athymic Foxn1^−/− mice—and exhibit a surface phenotype distinct from CD127⁻ NK and thymus-derived CD127⁺ NK cells. Functional assays demonstrated that CD127⁺ NK cells produce interferon-γ and exert cytotoxic activity, despite expressing markers typically associated with immature NK cells. CD127⁺ NK cells were absent in IL-7Rα^−/− mice but present in IL-15^−/− and IL-15Rα^−/− mice, indicating a selective dependence on IL-7 signaling. IL-7 promoted their proliferation and activation both in vitro and in vivo. These findings revise current models of NK cell development by identifying a novel, IL-7-responsive, IL-15-independent, thymus-independent, and functionally competent CD127⁺ NK cell subset that is phenotypically distinct from helper-like innate lymphoid cells (ILCs). This study provides a framework for future investigations on NK cell heterogeneity, tissue specialization, and cytokine-mediated regulation. Full article

Marine lectins function as pattern recognition receptors in innate immunity through carbohydrate-binding mechanisms. However, mechanistic evidence detailing intracellular signaling cascades (e.g., MAPK/NF-κB/JAK-STAT activation linked to defined cytokine outputs) remains taxonomically uneven. Bivalve mollusks—particularly the Mytilectin family—represent the most extensively characterized group, whereas lectins from other marine phyla (echinoderms, cnidarians, fish, algae) have been studied primarily for structural and glycan-binding properties alongside phenotypic antimicrobial outcomes. Signaling-level resolution in native immune-cell contexts, while present in some cases, remains comparatively limited. This review synthesizes mechanistic insights dominated by bivalve-derived lectins, while integrating cross-taxa comparisons at evidence-supported levels. Specific bivalve lectins induce macrophage activation and pro-inflammatory cytokine production through reactive oxygen species-dependent activation of key signaling pathways including MAPK, NF-κB, and JAK-STAT cascades. These lectins exhibit context-dependent properties, promoting inflammatory responses in resting cells while inducing endotoxin tolerance in pre-activated macrophages through epigenetic reprogramming. Functional outcomes include broad-spectrum antiviral activity through viral envelope glycoprotein binding, anti-inflammatory effects in pain models, and cancer-associated immune responses through tumor glycan recognition and macrophage polarization. Critical gaps include uncharacterized effects on adaptive immunity, limited understanding of dendritic cell and natural killer cell interactions, and incomplete evaluation of cancer immunotherapy potential. Future research should prioritize mechanistic characterization of marine lectin-based immunotherapeutics. Full article

CD57-expressing lymphocytes constitute a distinct subset of immune cells with enhanced cytotoxic and pro-inflammatory functions. Initially described in the context of chronic viral infections, most notably cytomegalovirus (CMV), these cells are now recognized as central contributors to immunosenescence and age-related immune dysregulation. Their progressive accumulation reflects prolonged antigenic exposure and sustained immune activation, thereby linking persistent viral infections with long-term disruptions of immune homeostasis. Emerging evidence indicates that CD57 expression denotes a state of terminal differentiation in both T and natural killer (NK) cell compartments, and is associated with cytotoxicity, altered cytokine secretion, and a pro-inflammatory phenotype. This review summarizes the phenotypic and functional characteristics of CD57⁺ lymphocytes, examines their association with CMV and other chronic viral infections, and explores their potential role in ageing and age-related diseases. Elucidating the biology of CD57⁺ lymphocytes in the context of chronic viral infections may provide novel insights into immune ageing and help identify potential targets for therapeutic strategies aimed at restoring immune balance in older adults. Full article