Search Results (46)

Lymphocyte activation gene-3 (LAG-3) is a pivotal immune checkpoint receptor that exerts a negative regulatory effect on T-cell function. Although LAG-3-blocking antibodies have shown promising clinical potential, the inherent limitations of conventional monoclonal antibodies necessitate the development of novel antibody formats with enhanced biological and pharmacological properties. In this study, a panel of single-domain antibodies (sdAbs) targeting human LAG-3 was generated via phage display technology. Among these candidates, 2H-G7 was identified as a high-affinity sdAb that binds to LAG-3 with an equilibrium dissociation constant (K_D) in the nanomolar range. Notably, 2H-G7 potently blocks the interactions of LAG-3 with both of its key ligands, fibrinogen-like protein 1 (FGL1) and major histocompatibility complex class II (MHC-II). Its capacity to restore impaired T-cell function was validated by quantifying interleukin-2 (IL-2) secretion and CD69 expression in stimulated primary human peripheral blood mononuclear cells (PBMCs). Epitope mapping studies localized the binding site of 2H-G7 to the D1D2 extracellular domains of LAG-3, distinct from relatlimab, a clinically approved LAG-3-blocking antibody serving as the benchmark. In a xenogeneic mouse model of non-small-cell lung cancer (NSCLC), 2H-G7-Fc exhibited superior tumor growth inhibition efficacy compared with relatlimab. These findings demonstrate that 2H-G7 is a promising lead candidate for the development of next-generation LAG-3-targeted tumor immunotherapies. Full article

This study aimed to elucidate the key characteristics of the humoral immune response and the tissue distribution of specific antibody-secreting cells (ASCs) in Nile tilapia (Oreochromis niloticus). A specific immune model was established by immunizing fish with human IgG. Lymphocytes were isolated from the head kidney, spleen, and peripheral blood and subjected to antigen stimulation in vitro. The MTT assay, reflecting cell metabolic activity and viability, identified the optimal culture conditions as a cell concentration of 2.5 × 10⁶ cells/mL, an antigen concentration of 2 μg/mL, and a culture duration of 72 h. Under these conditions, peripheral blood lymphocytes exhibited the most increase in metabolic activity, followed by head kidney lymphocytes, while splenic lymphocytes showed no significant response. Subsequent dynamic monitoring of antibody-secreting cells (ASCs) using ELISPOT revealed that, in the absence of antigen stimulation, ASC numbers from all three tissues declined over time. Notably, head kidney ASCs retained approximately 50% of their initial number by day 5, whereas ASCs in peripheral blood and spleen decayed to barely detectable or completely undetectable levels, respectively. These findings suggest that the head kidney may serve as a primary site for ASC persistence during the effector phase, potentially contributing to sustained humoral immunity. Although antigen stimulation did not induce significant ASC expansion, it significantly slowed their decay rate (p < 0.05), indicating an antigen-dependent maintenance role. ELISA detection of antibody levels in the culture supernatants showed a consistent trend with the ELISPOT results, further confirming the sustained functional support of antigen for ASCs. Additionally, LPS stimulation experiments demonstrated that all three tissues contained plasmablasts activatable by non-specific stimuli, with peripheral blood showing the highest proliferation fold (4–6 times). In conclusion, this study provides insights into the tissue-specific distribution, in vitro persistence, and antigen-dependent maintenance of ASCs in Nile tilapia, providing insights into the cellular basis that may contribute to humoral immune memory and laying a theoretical foundation for the rational design and application of tilapia vaccines. Full article

Belimumab, a fully humanized B cell-activating factor (BAFF)-targeting monoclonal antibody, inhibits autoreactive B cell survival and improves systemic lupus erythematosus (SLE) clinical outcomes. However, its administration criteria remain unclear. To establish a basis for defining these criteria, we characterized the immune cell subpopulation alterations post-belimumab treatment and elucidated the underlying mechanisms. We hypothesized that belimumab modulates specific cell subsets and investigated the post-therapy changes. Flow cytometry and correlation analysis revealed that the frequency of B- and T-lymphocyte attenuator (BTLA)^high memory B cells in peripheral blood and clinical improvement after belimumab treatment. Western blotting analysis of healthy control B cells revealed that BTLA engagement suppressed Bruton tyrosine kinase and phospholipase C-gamma 2 phosphorylation, which was enhanced by B cell and BAFF receptor co-stimulation. BTLA-expressing memory B cells, which positively correlate with disease improvement, possibly contributed to SLE improvement via BTLA-mediated signaling that attenuated B cell- and BAFF receptor-induced intracellular pathways. To validate these findings, we plan to further assess the effects of belimumab on BTLA expression and B cell signaling pathways in treatment-naive patients with SLE by western blotting. Collectively, our results provide a novel foundation for establish appropriate belimumab administration criteria. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with limited responsiveness to immune checkpoint inhibitors (ICIs). Cancer vaccine therapy is a promising novel immunotherapeutic approach that stimulates tumor-specific T cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is overexpressed in malignant tumors but minimally expressed in normal tissues, presents a promising target for immunotherapy. This study aimed to evaluate ROR1 as a target for helper T lymphocyte (HTL)-based peptide vaccine immunotherapy in HNSCC. Methods: ROR1 expression in HNSCC tissues was assessed by immunohistochemistry. A novel ROR1-derived epitope (ROR1_403–417) was identified and used to generate ROR1-reactive HTLs. Functional assays measuring IFN-γ and granzyme B secretion, as well as direct cytotoxicity, were performed. The effects of ICIs on HTL activity were also examined. The presence of ROR1-reactive T cells in the peripheral blood of patients with HNSCC was evaluated. Results: ROR1 positivity rates in HNSCC tissues were significantly higher (80.0%) than those in healthy controls (16.7%), and high ROR1 expression correlated with advanced clinical stages. HTL lines recognized the ROR1_403–417 peptide in a human leukocyte antigen (HLA)-DR-restricted manner, secreted effector cytokines, and exhibited direct cytotoxicity against ROR1+ tumor cells. Dual PD-L1/PD-L2 blockade further enhanced HTL responses. ROR1-reactive T cells were detected in the peripheral blood of patients with HNSCC. Conclusions: ROR1 represents a promising target for immunotherapy in HNSCC. The ROR1_403–417 peptide can elicit ROR1-reactive HTLs that exhibit antitumor responses against HNSCC cell lines, which can be enhanced by ICIs. These findings support the potential of ROR1-targeted peptide vaccine therapy for HNSCC. Full article

(6S,9R)-vomifoliol (VO) is a natural norisoprenoid of the megastigmane type derived from Gaultheria procumbens, an aromatic, evergreen shrub whose leaves, fruits, and aerial parts are used in traditional phytotherapy to treat oxidative stress and inflammation-related disorders. The plant is known as a rich source of essential oil and polyphenols. However, the levels of other constituents of G. procumbens, including VO, have yet to be explored. There is also a knowledge gap in the pharmacological potential of VO in the context of inflammation. Therefore, the present study aimed to investigate the accumulation of VO in leaves, stems, and fruits of G. procumbens and to determine its antioxidant and anti-inflammatory effects in non-cellular in vitro and cell-based models of human immune cells ex vivo. The GC-FID-MS (gas chromatography coupled with flame ionisation detector and mass spectrometer) analysis revealed the leaves as the richest source of VO (0.36 mg/g dw of the plant material) compared to other G. procumbens organs. In non-cellular activity tests, VO showed comparable to positive control anti-inflammatory activity against lipoxygenase, with significantly weaker impact on hyaluronidase and cyclooxygenase-2, and no effect on cyclooxygenase-1 isozyme. VO at 5–75 μM revealed a significant and dose-dependent ability to reduce the reactive oxygen species (ROS) level, downregulate the release of pro-inflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8), IL-6, and IL-1β] and tissue-remodelling enzymes (elastase-2, metalloproteinase-9), and up-regulate the secretion of anti-inflammatory cytokine IL-10 in bacterial lipopolysaccharide (LPS)- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-stimulated human neutrophils and peripheral blood mononuclear cells (PBMCs) ex vivo. Furthermore, a significant reduction in IL-6, lipoxygenase (LOX), nuclear factor κ-light-chain-enhancer of activated B cells 1 (NF-κB1), and NF-κB2 gene expression in LPS-stimulated peripheral blood lymphocytes was demonstrated by real-time PCR. The cellular safety of VO at 5–75 μM was confirmed by flow cytometry, with the viability of neutrophils and PBMCs after incubation with VO at 93.8–98.4%. The results encourage further studies of VO as a promising non-cytotoxic natural anti-inflammatory agent and support the use of leaves of G. procumbens in the adjuvant treatment of oxidative stress and inflammation-related diseases of affluence. Full article

The cytotoxic T lymphocyte-associated antigen-4 (CTLA4) gene, a member of the immunoglobulin superfamily, is crucial for maintaining immune homeostasis and preventing autoimmune diseases. Studies have shown that polymorphisms in the CTLA4 gene are linked to an increased risk of brucellosis in humans, but its association with brucellosis in goats remains unexplored. In this study, the tissue expression profile of CTLA4 in goats was investigated, and the correlation between InDel polymorphisms in the CTLA4 gene and susceptibility to brucellosis in goats was examined. The findings reveal the widespread expression of CTLA4 in goat tissues, particularly in the spleen and testes. The tested goat populations presented genotypes insertion/insertion (II), insertion/deletion (ID), and deletion/deletion (DD) at both the P1 and P2 loci, and an association analysis revealed significant differences in the distribution of genotypes and allele frequencies at the P1 and P2 loci of the CTLA4 gene between the Brucella goat case and the control groups (p < 0.05). Specifically, compared with the II genotype, the P1 and P2 loci were significantly associated with an elevated risk of brucellosis development in goats under both the codominant (ID/II) and dominant (ID + DD/II) models (P1, p = 0.042, p = 0.016; P2, p = 0.011, p = 0.014). Additionally, haplotype analysis indicated that haplotypes I_P1D_P2, D_P1I_P2, and D_P1D_P2 were significantly associated with an increased risk of brucellosis in goats compared to the reference haplotype I_P1I_P2 (p = 0.029, p = 0.012, p = 0.034). Importantly, the Lipopolysaccharide (LPS) stimulation of peripheral blood monocytes and/or macrophages from goats with the II, ID, and DD genotypes resulted in increased CTLA4 expression levels in the II genotype, leading to a robust LPS-induced inflammatory response. Through bioinformatic analysis, the observed effect of the InDel locus on Brucella pathogenesis risk in goats could be attributed to the differential binding of the transcription factors nuclear factor kappaB (NF-κB) and CCAAT/enhancer-binding protein α (C/EBPα). These findings offer potential insights for breeding strategies against brucellosis. Full article

Background/Objectives: Oncolytic virotherapy is a promising approach in cancer immunotherapy. We have previously described a recombinant hybrid oncolytic virus (OV), VSV-NDV, which has a favorable safety profile and therapeutic immunogenicity, leading to direct oncolysis, abscopal effects, and prolonged survival in syngeneic in vivo tumor models. While OVs are known to mediate systemic anti-tumor immune responses, the detailed characterization of local and systemic immune responses to fusogenic oncolytic virotherapy remains unexplored. Methods and Results: We analyzed immune cell compartments in the spleen, blood, tumor-draining lymph nodes (TDLNs), and tumors over the course of VSV-NDV therapy in a bilateral syngeneic melanoma mouse model. Our results revealed significant local infiltration and activation of T lymphocytes in tumors and globally in the blood and spleen. Notably, in vivo CD8⁺ T cell depletion led to complete abrogation of the tumor response, highlighting the crucial role of T cells in promoting the therapeutic effects of oncolytic VSV-NDV. In vitro co-culture experiments enabled the interrogation of human immune cell responses to VSV-NDV-mediated oncolysis. Human peripheral blood mononuclear cells (PBMCs) were efficiently stimulated by exposure to VSV-NDV-infected cancer cells, which recapitulates the in vivo murine findings. Conclusions: Taken together, these data characterize a broad anti-tumor immune cell response to oncolytic VSV-NDV therapy and suggest that CD8⁺ T cells play a decisive role in therapeutic outcome, which supports the further development of this chimeric vector as a multimechanistic immunotherapy for solid cancers. Full article

IL-15 is a homeostatic cytokine for human T and NK cells. However, whether other cytokines influence the effect of IL-15 is not known. We studied the impact that IL-10, TGF-β, IL-17A, and IFN-γ have on the IL-15-induced proliferation of human T cells and the expression of HLA class I (HLA-I) molecules. Peripheral blood lymphocytes (PBLs) were labeled with CFSE and stimulated for 12 days with IL-15 in the absence or presence of the other cytokines. The proportion of proliferating T cells and the expression of cell surface HLA-I molecules were analyzed using flow cytometry. The IL-15-induced proliferation of T cells was paralleled by an increase in the expression of HC-10-reactive HLA-I molecules, namely on T cells that underwent ≥5–6 cycles of cell division. It is noteworthy that the IL-15-induced proliferation of T cells was potentiated by IL-10 and TGF-β but not by IL-17 or IFN-γ and was associated with a decrease in the expression of HC-10-reactive molecules. The cytokines IL-10 and TGF-β potentiate the proliferative capacity that IL-15 has on human T cells in vitro, an effect that is associated with a reduction in the amount of HC-10 reactive HLA class I molecules induced by IL-15. Full article

Human T-cell leukemia virus type-1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The trans-activator protein Tax of HTLV-1 plays crucial roles in leukemogenesis by promoting proliferation of virus-infected cells through activation of growth-promoting genes. However, critical target genes are yet to be elucidated. We show here that Tax activates the gene coding for cyclin-dependent kinase 7 (CDK7), the essential component of both CDK-activating kinase (CAK) and general transcription factor TFIIH. CAK and TFIIH play essential roles in cell cycle progression and transcription by activating CDKs and facilitating transcriptional initiation, respectively. Tax induced CDK7 gene expression not only in human T-cell lines but also in normal peripheral blood lymphocytes (PHA-PBLs) along with increased protein expression. Tax stimulated phosphorylation of CDK2 and RNA polymerase II at sites reported to be mediated by CDK7. Tax activated the CDK7 promoter through the NF-κB pathway, which mainly mediates cell growth promotion by Tax. Knockdown of CDK7 expression reduced Tax-mediated induction of target gene expression and cell cycle progression. These results suggest that the CDK7 gene is a crucial target of Tax-mediated trans-activation to promote cell proliferation by activating CDKs and transcription. Full article

Pygeum africanum bark has been shown to inhibit the production of pro-inflammatory prostaglandins in the prostate and reduces the production of leukotrienes and other 5-lipoxygenase (5-LO) metabolites. It has been suggested that inflammation plays an important role in the pathophysiology of benign prostatic hyperplasia (BPH). Data from clinical trials have shown that P. africanum improves the symptoms and objective measures of BPH. This in vitro study aimed to assess the anti-inflammatory potential of a proprietary Pygeum bark standardized extract (Prunera^®) on cytokine release from lipopolysaccharide-stimulated human peripheral blood mononuclear cells (PBMCs). PBMCs were obtained from four donors, and a bead-based assay (ProcartaPlex™ panel) was used for the detection and quantitation of cytokines. Pygeum africanum bark standardized extract (PABE) induced a statistically significant decrease (p < 0.05) of IL-6 in three donors. Other effects were as follows: IL-2 was lowered in all donors in the absence of a clear dose–response relationship; IL-4, IL-5, IL-9, and IL-13 levels were decreased in most donors; IL-22 levels seemed to be suppressed only for donor 4 at lower and medium concentrations; and IL-27 and TNF-α levels decreased at all PABE concentrations in all donors. The anti-inflammatory effect of PABE, particularly the reduction in IL-6 as a marker of inflammation, supports the potential use of this natural compound in the management of BPH and other conditions in which pro-inflammatory cytokines are involved in their underlying pathophysiological mechanisms. Full article

Background: Gastric cancer, ranked as the fifth most common cancer worldwide, presents multiple treatment challenges. These obstacles often arise due to cancer stem cells, which are associated with recurrence, metastasis, and drug resistance. While dendritic cell (DC)-based immunotherapy has shown promise as a therapeutic strategy, its efficacy can be limited by the tumor microenvironment and certain inhibitory immune checkpoint molecules, such as B7H7. SiRNA-medicated knockdown of B7H7 in tumor cell lysate-pulsed DCs can increase cytokine secretion and autologous T lymphocyte expansion. This study aimed to evaluate the impact of B7H7 suppression in gastric cancer cell lysate-pulsed DCs on the stimulatory potential of autologous CD3⁺ T lymphocytes. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated and monocytes were obtained; then, they were differentiated to immature DCs (iDCs) by GM-CSF and IL-4. Tumor cell lysates from human gastric cancer cell lines were harvested, and iDCs were transformed into mature DCs (mDCs) by stimulating iDCs with tumor cell lysate and lipopolysaccharide. B7H7-siRNA was delivered into mDCs using electroporation, and gene silencing efficiency was assessed. The phenotypic characteristics of iDCs, mDCs, and B7H7-silenced mDCs were evaluated using specific surface markers, an inverted light microscope, and flow cytometry. CD3⁺ T cells were isolated via magnetically activated cell sorting. They were labeled with CFSE dye and co-cultured with mDCs and B7H7-silenced mDCs to evaluate their ability to induce T-cell proliferation. T-cell proliferation was assessed using flow cytometry. The concentration of TGF-β, IL-4, and IFN-γ secreted from CD3⁺ T cells in the co-cultured supernatant was evaluated to investigate the cytokine secretory activity of the cells. Results: Transfection of B7H7 siRNA into mDCs was performed in optimal conditions, and the siRNA transfection effectively reduced B7H7 mRNA expression in a dose-dependent manner. SiRNA-mediated B7H7 knockdown in mDCs enhanced maturation and activation of the DCs, as demonstrated by an increased surface expression of CD11c, CD86, and CD40. Co-culture experiments revealed that B7H7-silenced mDCs had more capacity to induce T cell proliferation compared to non-transfected mDCs. The cytokine production patterns of T cells were also altered. Upon examining the levels of TGF-β, IL-4, and IFN-γ released by CD3⁺ T cells in the co-culture supernatant, we found that silencing B7H7 in mDCs resulted in a rise in IL-4 secretion and a reduction in TGF-β levels compared to mDCs that were not transfected. Conclusions: The study found that suppressing B7H7 expression in DCs significantly enhances their maturation and stimulatory activity when exposed to gastric cancer cell lysate. These B7H7-silenced DCs can substantially increase cytokine production and promote co-cultured T-cell expansion. Consequently, inhibiting B7H7 in DCs may offer a practical strategy to enhance the ability of DCs to initiate T lymphocyte responses and improve the effectiveness of DC-based cell therapy for cancer patients. Full article

Pathogenic microbes use arginine-metabolizing enzymes as an immune evasion strategy. In this study, the impact of streptococcal arginine deiminase (ADI) on the human peripheral blood T lymphocytes function in vitro was studied. The comparison of the effects of parental strain (Streptococcus pyogenes M49-16) with wild type of ArcA gene and its isogenic mutant with inactivated ArcA gene (Streptococcus pyogenes M49-16delArcA) was carried out. It was found that ADI in parental strain SDSC composition resulted in a fivefold decrease in the arginine concentration in human peripheral blood mononuclear cell (PBMC) supernatants. Only parental strain SDSCs suppressed anti-CD2/CD3/CD28-bead-stimulated mitochondrial dehydrogenase activity and caused a twofold decrease in IL-2 production in PBMC. Flow cytometry analysis revealed that ADI decreased the percentage of CM (central memory) and increased the proportion of TEMRA (terminally differentiated effector memory) of CD4+ and CD8+ T cells subsets. Enzyme activity inhibited the proliferation of all CD8+ T cell subsets as well as CM, EM (effector memory), and TEMRA CD4+ T cells. One of the prominent ADI effects was the inhibition of autophagy processes in CD8+ CM and EM as well as CD4+ CM, EM, and TEMRA T cell subsets. The data obtained confirm arginine’s crucial role in controlling immune reactions and suggest that streptococcal ADI may downregulate adaptive immunity and immunological memory. Full article

Thymalin is an immunomodulatory drug containing a polypeptide extract of thymus that has demonstrated efficacy in the therapy of acute respiratory distress syndrome and chronic obstructive pulmonary disease, as well as in complex therapy related to severe COVID-19 in middle-aged and elderly patients.. KE and EW dipeptides are active substances of Thymalin. There is evidence that KE stimulates cellular immunity and nonspecific resistance in organisms, exerting an activating effect on macrophages, blood lymphocytes, thymocytes, and neutrophils, while EW reduces angiotensin-induced vasoconstriction and preserves endothelium-dependent vascular relaxation by inhibiting ACE2, the target protein of SARS-CoV-2. However, the mechanism of the immunomodulatory action of Thymalin, KE, and EW during COVID-19 remains unclear. To identify the potential mechanism of action underlying the immunomodulatory activity of Thymalin and its active components, EW and KE dipeptides, we assessed inflammatory response in the context of COVID-19. Interactions between EW and KE dipeptides and double-stranded DNA (dsDNA) were investigated by molecular modeling and docking using ICM-Pro. Analysis of the possible effect of EW and KE dipeptides on gene expression and protein synthesis involved in the pathogenesis of COVID-19 was conducted through the use of bioinformatics methods, including a search for promoter sequences in the Eukaryotic Promoter Database, the determination of genes associated with the development of COVID-19 using the PathCards database of human biological pathways (pathway unification database), identification of the relationship between proteins through cluster analysis in the STRING database (‘Search Tool for Retrieval of Interacting Genes/Proteins’), and assessment of the functional enrichment of protein–protein interaction (PPI) using the terms of gene ontology (GO) and the Markov cluster algorithm (MCL). After that, in vitro studying of a lipopolysaccharide (LPS)-induced model of inflammation using human peripheral blood mononuclear cells was performed. ELISA was applied to assess the level of cytokines (IL-1β, IL-6, TNFα) in the supernatant of cells with or without the impact of EW and KE peptides. Blood samples were obtained from four donors; for each cytokine, ELISA was performed 2–4 times, with two parallel experimental or control samples for each experiment (experiments to assess the effects of peptides on LPS-stimulated cells were repeated four times, while additional experiments with unstimulated cells were performed two times). Using molecular docking, GGAG was found to be the best dsDNA sequence in the classical B-form for binding the EW dipeptide, while GCGC is the preferred dsDNA sequence in the curved nucleosomal form for the KE dipeptide. Cluster analysis revealed that potential target genes for the EW and KE peptides encode the AKT1 and AKT2 proteins involved in the development of the cytokine storm. The specific targets for the EW peptide are the ACE2 and CYSLTR1 genes, and specific target for the KE peptide is the CHUK gene. Protein products of the ACE2, CYSLTR1, and CHUK genes are functionally associated with IL-1β, IL-6, TNF-α, IL-4, and IL-10 cytokines. An in vitro model of an inflammatory reaction demonstrated that Thymalin and EW and KE dipeptides reduced the synthesis of IL-1β, IL-6, and TNF-α cytokines in human peripheral blood mononuclear cells by 1.4–6.0 times. The immunomodulatory effect of Thymalin under the inflammatory response conditions in COVID-19 is based on the potential ability of its active components, EW and KE dipeptides, to regulate protein synthesis involved in the development of the cytokine storm. Full article

Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (GHR). A GHR-knockout (GHR-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in GHR-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4⁻ and CD4⁺ lymphocytes and IFN-α serum levels between wild-type (WT) controls and GHR-KO pigs, which revealed significant differences in the relative proportion of the CD4⁺CD8α⁻ subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4⁺ and CD4⁻ lymphocyte populations revealed multiple significant protein abundance differences between GHR-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of GHR-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions. Full article

Oral lichen planus (OLP) is a chronic T cell-mediated inflammatory disease. Interferon (IFN)-γ has been suggested to be vital for the OLP immune responses. A prominent innate-like lymphocyte subset, γδ T cells, span the innate–adaptive continuum and exert immune effector functions by producing a wide spectrum of cytokines, including IFN-γ. The involvement and mechanisms of γδ T cells in the pathogenesis of OLP remain obscure. The expression of γδ T cells in lesion tissues and in the peripheral blood of OLP patients was determined via flow cytometry and immunohistochemistry, respectively. Human leukocyte antigen-DR (HLA-DR), cluster of differentiation (CD) 69, Toll-like receptors (TLRs), natural killer group 2, member D (NKG2D) and IFN-γ were detected in γδ T cells of OLP patients using flow cytometry. Additionally, the involvement of stimulator of the interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway in γδ T cells was evaluated by multi-color immunofluorescence. Western blotting was employed to investigate the regulatory mechanisms of γδ T cells in OLP. γδ T cells were significantly upregulated in the lesion tissues, whereas their peripheral counterparts were downregulated in OLP patients. Meanwhile, increased frequencies of local CD69⁺ and NKG2D⁺ γδ T cells and peripheral HLA-DR⁺ and TLR4⁺ γδ T cells were detected in OLP. Furthermore, significant co-localization of STING and TBK1 was observed in the γδ T cells of OLP lesions. In addition, enhanced IFN-γ and interleukin (IL)-17A were positively associated with the activated STING-TBK1 pathway and γδ T cells in OLP. Taken together, the upregulated STING-TBK1 pathway in activated γδ T cells might participate in the regulation of immune responses in OLP. Full article