Γδ T Cells Research Articles

The roles of IRF8 in nonspecific orbital inflammation: an integrated analysis by bioinformatics and machine learning

BackgroundNonspecific Orbital Inflammation (NSOI) represents a persistent and idiopathic proliferative inflammatory disorder, characterized by polymorphous lymphoid infiltration within the orbit. The transcription factor Interferon Regulatory Factor 8 (IRF8), integral to the IRF protein family, was initially identified as a pivotal element for the commitment and differentiation of myeloid cell lineage. Serving as a central regulator of innate immune receptor signaling, IRF8 orchestrates a myriad of functions in hematopoietic cell development. However, the intricate mechanisms underlying IRF8 production remain to be elucidated, and its potential role as a biomarker for NSOI is yet to be resolved.MethodsIRF8 was extracted from the intersection analysis of common DEGs of GSE58331 and GSE105149 from the GEO and immune- related gene lists in the ImmPort database using The Lasso regression and SVM-RFE analysis. We performed GSEA and GSVA with gene sets coexpressed with IRF8, and observed that gene sets positively related to IRF8 were enriched in immune-related pathways. To further explore the correlation between IRF8 and immune-related biological process, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate TME characteristics of each sample and confirmed that high IRF8 expression might give rise to high immune cell infiltration. Finally, the GSE58331 was utilized to confirm the levels of expression of IRF8.ResultsAmong the 314 differentially expressed genes (DEGs), some DEGs were found to be significantly different. With LASSO and SVM-RFE algorithms, we obtained 15 hub genes. For biological function analysis in IRF8, leukocyte mediated immunity, leukocyte cell-cell adhesion, negative regulation of immune system process were emphasized. B cells naive, Macrophages M0, Macrophages M1, T cells CD4 memory activated, T cells CD4 memory resting, T cells CD4 naive, and T cells gamma delta were shown to be positively associated with IRF8. While, Mast cells resting, Monocytes, NK cells activated, Plasma cells, T cells CD8, and T cells regulatory (Tregs) were shown to be negatively linked with IRF8. The diagnostic ability of the IRF8 in differentiating NSOI exhibited a good value.ConclusionsThis study discovered IRF8 that are linked to NSOI. IRF8 shed light on potential new biomarkers for NSOI and tracking its progression.

Establishing a Ten Disulfidptosis-related Gene Signature for Prognostic Prediction in Skin Cutaneous Melanoma.

Disulfidptosis is a new metabolic-related regulated cell death associated with cancer growth. This study aimed to investigate the molecular mechanisms associated with disulfidptosis in skin cutaneous melanoma (SKCM) and establish a disulfidptosis-related gene signature for prognostic prediction in SKCM. Disulfidptosis-associated genes were identified from RNA-seq data of SKCM. A risk score signature was developed and validated through univariate Cox and LASSO analyses. Additionally, the immune microenvironment related to the risk score signature was investigated. Finally, a disulfidptosis-related genes-transcription factor -miRNA network was developed, and the expression levels of five disulfidptosis-related genes were initially verified in SKCM cell lines. A total of 107 disulfidptosis-related differentially expressed genes in SKCM samples were identified. A ten-disulfidptosis-gene signature was established, including BIN2, CCL3L3, CCL8, CD79A, CIITA, CXCR3, DEFB1, GPR171, IL2RB, and SOCS1. The SKCM samples were divided into high- and low-risk groups, of which samples in the low-risk group showed better survival performance. The receiver operating characteristic curve analysis confirmed the good potency of the disulfidptosis-related gene prognostic model. Except for DEFB1, the other nine genes were positively related with T cell CD8+, T cell CD4+ memory activated, T cell gamma delta, NK cell activated, and macrophage M1, and they were all negatively related with NK cell resting, macrophage M0, macrophage M2, and mast cell activated. Finally, we verified downregulated levels of SOCS1 and DEFB1 and upregulated CXCR3, BIN2, and CCL3L3 in A875 and A375. We successfully established ten disulfidptosis-related genes' prediction prognostic signatures for SKCM patients.

The therapeutic role of γδT cells in TNBC.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that presents significant therapeutic challenges due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. As a result, conventional hormonal and targeted therapies are largely ineffective, underscoring the urgent need for novel treatment strategies. γδT cells, known for their robust anti-tumor properties, show considerable potential in TNBC treatment as they can identify and eliminate tumor cells without reliance on MHC restrictions. These cells demonstrate extensive proliferation both in vitro and in vivo, and can directly target tumors through cytotoxic effects or indirectly by promoting other immune responses. Studies suggest that expansion and adoptive transfer strategies targeting Vδ2 and Vδ1 γδT cell subtypes have shown promise in preclinical TNBC models. This review compiles and discusses the existing literature on the primary subgroups of γδT cells, their roles in cancer therapy, their contributions to tumor cell cytotoxicity and immune modulation, and proposes potential strategies for future γδT cell-based immunotherapies in TNBC.

Dysregulation of Gamma Delta T-Cells, CD8+ T Cells, CD4+ T Cells, and Natural Killer Cells in Brain Pathology: Understanding HIV-Induced Impairment and Exploring Targeted GSH Therapy.

This review comprehensively explores the dysregulation of Gamma Delta T-cells, CD8+ T Cells, and Natural Killer T Cells in the context of Human Immunodeficiency Virus (HIV) infection and its implications for brain pathology. It encompasses an overview of the HIV disease process, immune cell dysregulation, association with neurological diseases, and the critical role of Glutathione (GSH) in T-cell function. The alterations in Gamma Delta T-cells during chronic infection, the intricate dynamics of Vδ1 and Vδ2 subsets, and the potential of Vγ9Vδ2 T cells in inhibiting HIV replication are discussed. Additionally, the review addresses the exhaustion, impaired cytotoxicity, and premature senescence of CD8+ T cells, as well as the dysregulation of Natural Killer Cells (NKCs) and their impact on overall immune system activity. Furthermore, it examines the role of Gamma Delta (γδ) T-cells in brain injuries, infections, and tumors and highlights the therapeutic implications of elevated GSH levels in promoting a T helper 1 (Th1) immune response. However, HIV-infected patients with decreased GSH exhibit a T helper 2 (Th2) bias, compromising protection against intracellular pathogens. Finally, the review discusses studies in murine models demonstrating the impact of GSH levels on immune responses and underscores the therapeutic potential of targeting GSH to enhance immunity in HIV patients. Overall, this review provides valuable insights into the complex interplay between immune dysregulation, GSH levels, and HIV-associated brain pathology, offering insights into potential therapeutic avenues for mitigating immune compromise and neurological impairments in HIV patients.

EVICTION study: ICT01, an anti-Butyrophilin 3A monoclonal antibody activating γ9δ2 T cells in combination with pembrolizumab in checkpoint inhibitor refractory melanoma.

9534 Background: γ9δ2 T-cell tumor infiltration is associated with a favorable prognosis making these cells a new potential target for immunotherapy. The anti-BTN3A mAb ICT01 selectively activates γ9δ2 T cells and is being studied in the phase1/2a EVICTION Trial (NCT04243499). In preclinical studies, ICT01 induces upregulation of PD-1 on γ9δ2 T-cells and combination with pembrolizumab leads to enhanced cancer cell killing, providing scientific rationale to evaluate this combination. Here we present interim results from EVICTION of ICT01 in combination with pembrolizumab in patients with checkpoint inhibitor (CPI) refractory melanoma. Methods: EVICTION evaluated ICT01 (20 µg to 200 mg, Q3W) plus pembrolizumab (200mg IV Q3W) in a dose escalation solid tumor basket design that resulted in an ongoing expansion cohort of patients with CPI refractory melanoma (2 dose levels, 7 and 200 mg ICT01). Patients are selected based on higher baseline γ9δ2 T cells. Efficacy evaluations by i/RECIST 1.1 are conducted every 8 weeks. Disease Control Rate (DCR) as primary efficacy endpoint is defined as the sum of complete response (CR), partial response (PR) and stable disease (SD, minimum week 16). Baseline and on-treatment blood and biopsy specimens are collected for correlative translational work. Results: ICT01 plus pembrolizumab has a favorable safety profile with first-dose Grade 1/2 infusion related reactions (IRR) and cytokine release syndrome (CRS) as most common adverse events (in 38% and 19% of patients respectively, 5%and 2% Grade 3) among all doses and indications. To date, 35 CPI refractory melanoma patients have been enrolled, of which 65% have received 2+ prior lines of CPI. Currently 21 patients are evaluable at week 16 with a DCR of 42% (including 3 PR) and a 6-month progression free survival of 38%. In the circulation, full BTN3A receptor occupancy on immune cells was achieved at 7 mg dose, with down-modulation of BTN3A observed at doses greater than 20 mg. Clinical response was related to baseline tumoral BTN3A expression, sustained elevation of IFNg levels, and tumor microenvironment remodeling, including increased PD-L1 expression and CD8 T cells proliferation and activation. Conclusions: ICT01 in combination with pembrolizumab has a favorable safety profile and promising efficacy data. Patient selection based on BTN3A tumor expression will be further evaluated as an enrichment strategy. Clinical trial information: NCT04243499 .

Phase I/II trial of LAVA-1207, a novel bispecific gamma-delta T-cell engager alone, or with low dose IL-2 or pembrolizumab, in metastatic castration resistant prostate cancer (mCRPC).

TPS2672 Background: LAVA-1207 is a humanized bispecific antibody that binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells and to prostate-specific membrane antigen (PSMA). It comprises a heterodimer of two fusion proteins, each consisting of a VHH linked to a human IgG1 Fc domain. Preclinical evidence demonstrates that, upon binding both targets, LAVA-1207 leads to potent Vγ9Vδ2-T cell degranulation and cytolytic activity against PSMA-expressing prostate cancer cells. IL-2 is an immune modulator which has been shown to support expansion of activated Vγ9Vδ2-T cells. PD-1 is an inhibitory immune checkpoint receptor that can dampen (Vγ9Vδ2-) T cell reactivity, suggesting that pembrolizumab could potentiate the effect of LAVA-1207. Methods: This trial is a phase 1/2a open label study with a 3+3 design in patients with refractory mCRPC to assess the safety of LAVA-1207 alone or with low dose IL-2 or with pembrolizumab, and to determine the recommended Phase 2a dose (RP2D). Secondary objectives include evaluation of pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity. Exploratory endpoints include evaluation of the effect of study treatment on circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). LAVA-1207 is administered IV every two weeks. Two parallel cohorts assessing LAVA-1207 with low dose subcutaneous IL-2 have been implemented: (1) single IL-2 administration and (2) three IL-2 administrations on consecutive days per cycle for up to four cycles. An additional dose escalation arm evaluates LAVA-1207 in combination with pembrolizumab, 400mg Q6W, IV. Patients with mCRPC that have failed at least one prior AR therapy and taxane-based chemotherapy (unless deemed medically unsuitable to receive a taxane) will be enrolled on the study. Patients should have progressive disease either by PSA or by RECIST 1.1 or appearance of 2 or more bone metastases. Patients must have ECOG performance status of 0-1. PSMA-PET is performed at baseline. Paired biopsies are requested to further assess LAVA-1207 activity. Dose escalation is ongoing. Expansion arm(s) will be included based on available data from part 1 of the study and may include one or more of LAVA-1207, LAVA-1207 with low dose IL-2, or LAVA-1207 in combination with pembrolizumab. Clinical trial information: NCT05369000 .

Mitochondrial function of dairy calf lymphocytes from birth to immunologic maturity

The inability of dairy calves to fully respond to immune stimuli until they reach maturity at 6 mo of age severely limits the use of parenteral vaccines to protect calves against disease. Immune responses are metabolically demanding, and immune cells rely on mitochondrial metabolites for their functionality. Due to the essential role of mitochondria in driving T-cell responses necessary for vaccine efficacy, we hypothesized that the mitochondrial function of dairy calf lymphocytes changes with age, from birth to immunologic maturity. In this cross-sectional study, groups of dairy calves (n = 4/group) were blood sampled at birth before colostrum intake and at 1, 2, 3, 4, 6, 8, 16, and 24 wk of age. Mid-lactation adult cows (n = 4) were also sampled to reference fully mature immune cell populations. B, CD4+, CD8+, and γδ T lymphocytes were enriched using magnetic-activated cell sorting, and their mitochondrial function was assessed with an extracellular flux analyzer. Non-mitochondrial oxygen consumption, basal respiration, maximal respiration, spare respiratory capacity, proton leak, and the oxygen consumption rate (OCR) to extracellular acidification rate (ECAR) ratio were reported. Results were compared among groups using a Kruskal-Wallis test. The OCR to ECAR ratio is an indicator of the relative proportions of oxidative phosphorylation and aerobic glycolysis which is associated with effector functions in lymphocytes. The ratio was lower in 0 wk than adults in CD4+ T-cells. For CD8+ T-cells, the OCR to ECAR ratio for the 2 wk group was lower than the 3 wk group. A lower OCR to ECAR ratio indicates more reliance on glycolytic metabolism than oxidative phosphorylation. Maximal respiration is an indication of mitochondrial efficiency and is often associated with mitochondrial mass. For γδ T-cells, the 3 wk group had higher maximal respiration than the 16 wk group, whereas for B cells maximal respiration was higher in the 1 wk compared with the 16 wk group. Basal respiration indicates all cell functions that require oxygen and was lower in the 0 wk group than the 1 wk and 3 wk groups for CD4+ T-cells. γδ T-cells exhibited lower basal respiration in the 2 wk group than the 24 wk one. Although we found minimal differences in the mitochondrial outcomes reported from non-stimulated lymphocytes from birth through 6 mo of age and mid-lactation adults who served as mature immune cell populations, these results align with previous reports from weaning aged calf and adult CD4+ T-cells. In conclusion, there was insufficient evidence to suggest that the mitochondria in the lymphocytes of dairy calves from birth through immunologic maturity had functional changes associated with age. In conclusion, the capacity of unstimulated calf mitochondria to perform oxidative phosphorylation is not associated with age.

IL-27 maintains cytotoxic Ly6C+ γδ T cells that arise from immature precursors

In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αβ-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C− cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C− cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C− cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology.

Camelid-derived Tcell engagers harnessing human γδ Tcells as promising antitumor immunotherapeutic agents.

In the last decade, there has been a surge in developing immunotherapies to enhance the immune system's ability to eliminate tumor cells. Bispecific antibodies known as Tcell engagers (TCEs) present an attractive strategy in this pursuit. TCEs aim to guide cytotoxic Tcells toward tumor cells, thereby inducing a strong activation and subsequent tumor cell lysis. In this study, we investigated the activity of different TCEs on both conventional alpha-beta (αβ) Tcells and unconventional gamma delta (γδ) Tcells. TCEs were built using camelid single-domain antibodies (VHHs) targeting the tumor-associated antigen CEACAM5 (CEA), together with Tcell receptor chains or a CD3 domain. We show that Vγ9Vδ2 Tcells display stronger in vitro antitumor activity than αβ Tcells when stimulated with a CD3xCEA TCE. Furthermore, restricting the activation of fresh human peripheral Tcells to Vγ9Vδ2 Tcells limited the production of protumor factors and proinflammatory cytokines, commonly associated with toxicity in patients. Taken together, our findings provide further insights that γδ Tcell-specific TCEs hold promise as specific, effective, and potentially safe molecules to improve antitumor immunotherapies.

Decoding Behcet's Uveitis: an In-depth review of pathogenesis and therapeutic advances.

Behcet's disease (BD) is a rare but globally distributed vasculitis that primarily affects populations in the Mediterranean and Asian regions. Behcet's uveitis (BU) is a common manifestation of BD, occurring in over two-thirds of the patients. BU is characterized by bilateral, chronic, recurrent, non-granulomatous uveitis in association with complications such as retinal ischemia and atrophy, optic atrophy, macular ischemia, macular edema, and further neovascular complications (vitreous hemorrhage, neovascular glaucoma). Although the etiology and pathogenesis of BU remain unclear, numerous studies reveal that genetic factors (such as HLA-B51), dysregulated immune responses of both the innate and adaptive immune systems, infections (such as streptococcus), and environmental factors (such as GDP) are all involved in its development. Innate immunity, including hyperactivity of neutrophils and γδT cells and elevated NK1/NK2 ratios, has been shown to play an essential role in this disease. Adaptive immune system disturbance, including homeostatic perturbations, Th1, Th17 overaction, and Treg cell dysfunction, is thought to be involved in BU pathogenesis. Treatment of BU requires a tailored approach based on the location, severity of inflammation, and systemic manifestations. The therapy aims to achieve rapid inflammation suppression, preservation of vision, and prevention of recurrence. Systemic corticosteroids combined with other immunosuppressive agents have been widely used to treat BU, and beneficial effects are observed in most patients. Recently, biologics have been shown to be effective in treating refractory BU cases. Novel therapeutic targets for treating BU include the LCK gene, Th17/Treg balance, JAK pathway inhibition, and cytokines such as IL-17 and RORγt. This article summarizes the recent studies on BU, especially in terms of pathogenesis, diagnostic criteria and classification, auxiliary examination, and treatment options. A better understanding of the significance of microbiome composition, genetic basis, and persistent immune mechanisms, as well as advancements in identifying new biomarkers and implementing objective quantitative detection of BU, may greatly contribute to improving the adequate management of BU patients.

Chemokine receptor 7 contributes to T- and B-cell filtering in ageing bladder, cystitis and bladder cancer

BackgroundResearch has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.MethodsBladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.ResultsEight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.ConclusionsIn this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.

A Low Number of Baselines γδ T Cells Increases the Risk of SARS-CoV-2 Post-Vaccination Infection.

Background: The COVID-19 pandemic is the biggest global health problem in the last hundred years. The efficacy of the vaccine to protect against severe disease is estimated to be 70-95% according to the studies carried out, although there are aspects of the immune response to the vaccine that remain unclear. Methods: Humoral and cellular immunity after the administration of three doses of the Pfizer-BioNTech and Oxford AstraZeneca vaccines against SARS-CoV-2 over one year and the appearance of post-vaccination COVID-19 were studied. SARS-CoV-2 IgG and IgA antibodies, αβ and γδ T-cell subsets, and their differentiation stages and apoptosis were analyzed. Results: Anti-SARS-CoV-2 IgG and IgA antibodies showed a progressive increase throughout the duration of the study. This increase was the greatest after the third dose. The highest levels were observed in subjects who had anti-SARS-CoV-2 antibodies prior to vaccination. There was an increase in CD4+ αβ, CD8+ γδ and TEM CD8+ γδ T cells, and a decrease in apoptosis in CD4+ CD8+ and CD56+ αβ and γδ T cells. Post-vaccination SARS-CoV-2 infection was greater than 60%. The symptoms of COVID-19 were very mild and were related to a γδ T cell deficit, specifically CD8+ TEMRA and CD56+ γδ TEM, as well as lower pre-vaccine apoptosis levels. Conclusions: The results unveil the important role of γδ T cells in SARS-CoV-2-vaccine-mediated protection from the disease.

Intermittent fasting alleviates IMQ-induced psoriasis-like dermatitis via reduced γδT17 and monocytes in mice.

Psoriasis is a chronic immune mediated inflammatory skin disease with systemic manifestations. It has been reported that caloric restriction could improve severity of psoriasis patients. However, the mechanism of intermittent fasting effects on psoriasis has not been investigated. Caloric restriction is known to reduce the number of circulating inflammatory monocytes in a CCL2-dependent manner. However, it is still unknown whether caloric restriction can improve psoriasis by regulating monocytes through CCL2. In this study, we used imiquimod (IMQ)-induced psoriasis-like mouse model to explore the effects and the mechanisms of intermittent fasting on psoriasis-like dermatitis. We found that intermittent fasting could significantly improve IMQ-induced psoriasis-like dermatitis, and reduce the number of γδT17 cells and IL-17 production in draining lymph nodes and psoriatic lesion via inhibiting proliferation and increasing death of γδT17 cells. Furthermore, intermittent fasting could significantly decrease monocytes in blood, and this was associated with decreased monocytes, macrophages and DC in psoriasis-like skin inflammation. Reduced monocytes in circulation and increased monocytes in BM of fasting IMQ-induced psoriasis-like mice is through reducing the production of CCL2 from BM to inhibit monocyte egress to the periphery. Our above data shads light on the mechanisms of intermittent fasting on psoriasis.

Arming Vδ2 T Cells with Chimeric Antigen Receptors to Combat Cancer.

Immunotherapy has emerged as a promising approach in the field of cancer treatment, with chimeric antigen receptor (CAR) T-cell therapy demonstrating remarkable success. However, challenges such as tumor antigen heterogeneity, immune evasion, and the limited persistence of CAR-T cells have prompted the exploration of alternative cell types for CAR-based strategies. Gamma delta T cells, a unique subset of lymphocytes with inherent tumor recognition capabilities and versatile immune functions, have garnered increasing attention in recent years. In this review, we present how arming Vδ2-T cells might be the basis for next-generation immunotherapies against solid tumors. Following a comprehensive overview of γδ T-cell biology and innovative CAR engineering strategies, we discuss the clinical potential of Vδ2 CAR-T cells in overcoming the current limitations of immunotherapy in solid tumors. Although the applications of Vδ2 CAR-T cells in cancer research are relatively in their infancy and many challenges are yet to be identified, Vδ2 CAR-T cells represent a promising breakthrough in cancer immunotherapy.

Analysis of the components of Mycobacterium tuberculosis heat-resistant antigen (Mtb-HAg) and its regulation of γδ T-cell function

BackgroundMycobacterium tuberculosis heat-resistant antigen (Mtb-HAg) is a peptide antigen released from the mycobacterial cytoplasm into the supernatant of Mycobacterium tuberculosis (Mtb) attenuated H37Ra strain after autoclaving at 121 °C for 20 min. Mtb-HAg can specifically induce γδ T-cell proliferation in vitro. However, the exact composition of Mtb-HAg and the protein antigens that are responsible for its function are currently unknown.MethodsMtb-HAg extracted from the Mtb H37Ra strain was subjected to LC‒MS mass spectrometry. Twelve of the identified protein fractions were recombinantly expressed in Escherichia coli by genetic engineering technology using pET-28a as a plasmid and purified by Ni–NTA agarose resin to stimulate peripheral blood mononuclear cells (PBMCs) from different healthy individuals. The proliferation of γδ T cells and major γδ T-cell subset types as well as the production of TNF-α and IFN-γ were determined by flow cytometry. Their proliferating γδ T cells were isolated and purified using MACS separation columns, and Mtb H37Ra-infected THP-1 was co-cultured with isolated and purified γδ T cells to quantify Mycobacterium viability by counting CFUs.ResultsIn this study, Mtb-HAg from the attenuated Mtb H37Ra strain was analysed by LC‒MS mass spectrometry, and a total of 564 proteins were identified. Analysis of the identified protein fractions revealed that the major protein components included heat shock proteins and Mtb-specific antigenic proteins. Recombinant expression of 10 of these proteins in by Escherichia coli genetic engineering technology was used to successfully stimulate PBMCs from different healthy individuals, but 2 of the proteins, EsxJ and EsxA, were not expressed. Flow cytometry results showed that, compared with the IL-2 control, HspX, GroEL1, and GroES specifically induced γδ T-cell expansion, with Vγ2δ2 T cells as the main subset, and the secretion of the antimicrobial cytokines TNF-α and IFN-γ. In contrast, HtpG, DnaK, GroEL2, HbhA, Mpt63, EsxB, and EsxN were unable to promote γδ T-cell proliferation and the secretion of TNF-α and IFN-γ. None of the above recombinant proteins were able to induce the secretion of TNF-α and IFN-γ by αβ T cells. In addition, TNF-α, IFN-γ-producing γδ T cells inhibit the growth of intracellular Mtb.ConclusionActivated γδ T cells induced by Mtb-HAg components HspX, GroES, GroEL1 to produce TNF-α, IFN-γ modulate macrophages to inhibit intracellular Mtb growth. These data lay the foundation for subsequent studies on the mechanism by which Mtb-HAg induces γδ T-cell proliferation in vitro, as well as the development of preventive and therapeutic vaccines and rapid diagnostic reagents.

Exercise-induced β2-adrenergic Receptor Activation Enhances the Antileukemic Activity of Expanded γδ T-Cells via DNAM-1 Upregulation and PVR/Nectin-2 Recognition.

Exercise mobilizes effector γδ T-cells to blood via β2-adrenergic signaling which allows for generation of a potent expanded γδ T-cell product that is highly cytotoxic against hematologic malignancies.

Proteomics screening after pediatric allogenic hematopoietic stem cell transplantation reveals an association between increased expression of inhibitory receptor FCRL6 on γδ Tcells and cytomegalovirus reactivation.

We studied the associations between inflammation-related proteins in circulation and complications after pediatric allogenic hematopoietic stem cell transplantation (HSCT), to reveal proteomic signatures or individual soluble proteins associated with specific complications after HSCT. We used a proteomics method called Proximity Extension Assay to repeatedly measure 180 different proteins together with clinical variables, cellular immune reconstitution and blood viral copy numbers in 27 children (1-18 years of age) during a 2-year follow-up after allogenic HSCT. Protein profile analysis was performed using unsupervised hierarchical clustering and a regression-based method, while the Bonferroni-corrected Mann-Whitney U-test was used for time point-specific comparison of individual proteins against outcome. At 6 months after allogenic HSCT, we could identify a protein profile pattern associated with occurrence of the complications such as chronic graft-versus-host disease, viral infections, relapse and death. When protein markers were analyzed separately, the plasma concentration of the inhibitory and cytotoxic T-cell surface protein FCRL6 (Fc receptor-like 6) was higher in patients with cytomegalovirus (CMV) viremia [log2-fold change 1.5 (P = 0.00099), 2.5 (P = 0.00035) and 2.2 (P = 0.045) at time points 6, 12 and 24 months]. Flow cytometry confirmed that FCRL6 expression was higher in innate-like γδ Tcells, indicating that these cells are involved in controlling CMV reactivation in HSCT recipients. In conclusion, the potentially druggable FCRL6 receptor on cytotoxic Tcells appears to have a role in controlling CMV viremia after HSCT. Furthermore, our results suggest that system-level analysis is a useful addition to the studying of single biomarkers in allogenic HSCT.

The role of γδT lymphocytes in atherosclerosis.

Atherosclerosis poses a significant threat to human health, impacting overall well-being and imposing substantial financial burdens. Current treatment strategies mainly focus on managing low-density lipids (LDL) and optimizing liver functions. However, it's crucial to recognize that Atherosclerosis involves more than just lipid accumulation; it entails a complex interplay of immune responses. Research highlights the pivotal role of lipid-laden macrophages in the formation of atherosclerotic plaques. These macrophages attract lymphocytes like CD4 and CD8 to the inflamed site, potentially intensifying the inflammatory response. γδ T lymphocytes, with their diverse functions in innate and adaptive immune responses, pathogen defense, antigen presentation, and inflammation regulation, have been implicated in the early stages of Atherosclerosis. However, our understanding of the roles of γδ T cells in Atherosclerosis remains limited. This mini-review aims to shed light on the characteristics and functions of γδ T cells in Atherosclerosis. By gaining insights into the roles of γδ T cells, we may uncover a promising strategy to mitigate plaque buildup and dampen the inflammatory response, thereby opening new avenues for effectively managing this condition.

T cell responses in immune-mediated IgA nephropathy.

Immunoglobulin A nephropathy is a complex autoimmune disease with various underlying causes and significant clinical heterogeneity. There are large individual differences in its development, and the etiology and pathogenesis are still poorly understood. While it is known that immunobiological factors play a significant role in the pathophysiology of immunoglobulin A nephropathy, the specific nature of these factors has yet to be fully elucidated. Numerous investigations have verified that CD4+ and CD8+ T lymphocytes are involved in the immunopathogenesis of immunoglobulin A nephropathy. Furthermore, certain data also point to γδT cells' involvement in the pathophysiology of immunoglobulin A nephropathy. By thoroughly examining the mechanisms of action of these T cells in the context of immunoglobulin A nephropathy, this review sheds light on the immunopathogenesis of the disease and its associated factors. The review is intended to provide reference value for the future research in this field and promising treatment clues for clinical patients.

Update on primary cutaneous T-cell lymphomas rare subtypes.

Rare subtypes of cutaneous T-cell lymphomas (CTCL) include four entities, primary cutaneous γδ T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorders, primary cutaneous acral CD8+ T-cell lymphoma, which were previously considered provisional and are now included in the new 5th World Health Organization classification of hematolymphoid tumors as distinct entities. An updated summary of the clinical, histological, and genomic characteristics of these uncommon CTCL subtypes is given in this review, with a focus on the growing body of knowledge regarding their classification and possible treatment strategies.