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The immune modulatory effects of vitamin D and the impact of vitamin D deficiency on various diseases are a subject of current scientific research. However, there are few data directly linking vitamin D to hard endpoints in clinical studies, apart from its well-known effects on bone health. It is therefore of interest, that the effectiveness of the therapeutic antibody rituximab is connected to the vitamin D serum level of patients with B cell lymphomas. Rituximab exerts its effect via antibody dependent cell mediated cytotoxicity (ADCC), with NK cells and γδ T cells acting as effector cells. Here we evaluated and compared how γδ T cells and NK cells are modified by long-term in vitro cultivation with calcitriol, the active metabolite of vitamin D. Peripheral blood mononuclear cells from healthy donors were stimulated in vitro with a combination of zoledronic acid (Zol) and interleukin-2 (IL-2) or with sole IL-2 and different concentrations of calcitriol were added to culture for up to 10 days. Our results confirmed the earlier reports of immune suppressive effects of calcitriol on immune cell proliferation and interferon-γ production. Under certain conditions, in vitro incubation with calcitriol led to an inhibited rituximab-mediated ADCC of Zol/IL-2 stimulated γδ T cells, but to an increased cytotoxic activity of IL-2 stimulated NK cells. This study directly shows immune modulatory activity of calcitriol on the cellular level and links vitamin D to anti-tumoral effects of NK and γδ T cells. [ABSTRACT FROM AUTHOR]

Lymphocytes of the gamma delta (γδ) T cell lineage are evolutionary conserved and although they express rearranged antigen-specific receptors a large proportion respond as innate effectors. γδ T cells are poised to combat infection by responding rapidly to cytokine stimuli similar to innate lymphoid cells. This potential to initiate strong inflammatory responses necessitates inhibitory signals are balanced with activation signals. Here, we discuss some of the key mechanisms that regulate the development, activation and inhibition of innate γδ T cells in light of recent evidence that the inhibitory Ig-superfamily member B and T lymphocyte attenuator (BTLA) restricts their differentiation and effector function.

Most circulating human gamma delta T cells are Vγ9Vδ2 T cells. Their hallmark is the expression of T cell antigen receptors (TCR) whose γ-chains show a Vγ9-JP (Vγ2-Jγ1.2) rearrangement and are paired with Vδ2 containing δ-chains, a dominant TCR configuration, which until recently seemed to occur in primates only. Vγ9Vδ2 T cells respond to phosphoantigens (PAg) such as (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) which is produced by many pathogens and isopentenyl pyrophosphate (IPP) which accumulates in certain tumors or cells treated with aminobisphosphonates such as zoledronate. A prerequisite for PAg-induced activation is the contact of Vγ9Vδ2 T cells with cells expressing butyrophilin 3 A1 (BTN3A1). We will first critically review models of how BTN3 might act in PAg-mediated Vγ9Vδ2 T cell activation and then address putative co-evolution of Vγ9, Vδ2 and BTN3 genes. In those rodent and lagomorphs used as animal models all three genes are lost but a data base analysis showed that they emerged together with placental mammals. A strong concomitant conservation of functional Vγ9, Vδ2 and BTN3 genes in other species suggests co-evolution of these three genes. A detailed analysis was performed for the new world camelid alpaca (Vicugna pacos). It provides an excellent candidate for a non-primate species with presumably functional Vγ9Vδ2 T cells since TCR rearrangements share features characteristic for PAg-reactive primate Vγ9Vδ2 TCR and proposed PAg-binding sites of BTN3A1 have been conserved. Finally, we analyze the possible functional relationship between the butyrophilin-family member Skint1 and the γδ TCR-V genes used by murine dendritic epithelial T cells (DETC). Among placental mammals, we identify 5 rodents, the cow, a bat and the cape golden mole as the only species concomitantly possessing potentially functional homologues of murine Vγ3, Vδ4 genes and Skint1 gene and suggest to search for DETC like cells in these species.

Introduction: Malignant pleural mesothelioma (MPM) is a rare and highly aggressive thoracic tumor with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors exhibit a promising effect in some patients with unresectable MPM in clinical trials, the majority of MPM patients show only modest response rates to the currently available treatments. It is thus imperative to develop novel and innovative therapeutic modalities for MPM, including immune effector cell-based therapies., Methods: γδ T cells were expanded using tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2, and the therapeutic potential of γδ T cells was examined through analyzing cell surface markers and cellular cytotoxicity against MPM in vitro using a europium chelate-based time-resolved fluorescence assay system and a luciferase-based luminescence assay system., Results and Discussion: We successfully expanded γδ T cells from peripheral blood mononuclear cells of healthy donors and MPM patients. γδ T cells expressed natural killer receptors such as NKG2D and DNAM-1 and exhibited a moderate level of cytotoxicity to MPM cells in the absence of antigens. The inclusion of PTA, ( E )-4-hydroxy-3- methylbut-2-enyl diphosphate (HMBPP) or zoledronic acid (ZOL) induced a TCR-dependent cytotoxicity in γδ T cells and secreted interferon-γ (IFN-γ). In addition, γδ T cells expressing CD16 exhibited a significant level of cytotoxicity against MPM cells in the presence of an anti-epidermal growth factor receptor (EGFR) mAb, at lower concentrations than in clinical settings, whereas a detectable level of IFN-γ was not produced. Taken together, γδ T cells showed cytotoxic activity against MPM in three distinct mechanisms through NK receptors, TCRs and CD16. Since major histocompatibility complex (MHC) molecules are not involved in the recognition, both autologous and allogeneic γδ T cells could be used for the development of γδ T cell-based adoptive immunotherapy for MPM., Competing Interests: YT is a co-inventor of Japanese Patent 2014-257451 on the development of the method to expand γδ T cells using PTA, a novel bisphosphonate prodrug and of Japanese Patent 2014-73475 on the development of a non-radioactive cellular cytotoxicity assay using BM-HT, a precursor of a novel Eu3+ chelate-forming compound. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Umeyama, Taniguchi, Gyotoku, Senju, Tomono, Takemoto, Yamaguchi, Tagod, Iwasaki, Tanaka and Mukae.)

Unlike conventional major histocompatibility complex (MHC) class I and II molecules reactive T cells, the unconventional T cell subpopulations recognize various non-polymorphic antigen-presenting molecules and are typically characterized by simplified patterns of T cell receptors (TCRs), rapid effector responses and 'public' antigen specificities. Dissecting the recognition patterns of the non-MHC antigens by unconventional TCRs can help us further our understanding of the unconventional T cell immunity. The small size and irregularities of the released unconventional TCR sequences are far from high-quality to support systemic analysis of unconventional TCR repertoire. Here we present UcTCRdb, a database that contains 669,900 unconventional TCRs collected from 34 corresponding studies in humans, mice, and cattle. In UcTCRdb, users can interactively browse TCR features of different unconventional T cell subsets in different species, search and download sequences under different conditions. Additionally, basic and advanced online TCR analysis tools have been integrated into the database, which will facilitate the study of unconventional TCR patterns for users with different backgrounds. UcTCRdb is freely available at http://uctcrdb.cn/., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dou, Shan and Zhang.)

Streptococcus pneumoniae is a pathogen of global morbidity and mortality. Pneumococcal pneumonia can lead to systemic infections associated with high rates of mortality. We find that, upon pneumococcal infection, pulmonary Treg cells are activated and have upregulated TNFR2 expression. TNFR2-deficient mice have compromised Treg cell responses and highly activated IL-17A-producing γδ T cell (γδT17) responses, resulting in significantly enhanced neutrophil infiltration, tissue damage, and rapid development of bacteremia, mirroring responses in Treg cell-depleted mice. Deletion of total Treg cells predominantly activate IFNγ-T cell responses, whereas adoptive transfer of TNFR2 + Treg cells specifically suppress the γδT17 response, suggesting a targeted control of γδT17 activation by TNFR2 + Treg cells. Blocking IL-17A at early stage of infection significantly reduces bacterial blood dissemination and improves survival in TNFR2-deficient mice. Our results demonstrate that TNFR2 is critical for Treg cell-mediated regulation of pulmonary γδT17-neutrophil axis, with impaired TNFR2 + Treg cell responses increasing susceptibility to disease., Competing Interests: Declaration of interests A.K. is the founder of ReNewVax Ltd and a member of its scientific advisory board., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The disorders of large granular lymphocytes include reactive proliferation as well as indolent or aggressive neoplasms of cytotoxic T cells, γδ T cells, and natural killer (NK) cells. They are associated with autoimmune and infectious disorders and have varied immunophenotypic features. We report a case, which highlights this complex association of autoimmune and infectious diseases with large granular lymphocytosis, the overlapping spectrum of large granular lymphocyte leukemias, and γδ T cell lymphomas as well as the difficulties in the diagnosis and management of these indolent T cell lymphomas in the usual clinical settings. [ABSTRACT FROM AUTHOR]

The term immunological memory has long been a trademark restricted to adaptive lymphocytes such as memory B cells and plasma cells as well as memory CD8+ αβ T cells. In recent years, innate lymphocytes such as NK cells have also been shown to adapt to their environment by antigen-specific expansion and selective survival. However, whether γδ T cells mount comparable memory responses to pathogenic stimuli is less well understood. In this issue of European Journal of Immunology, Hartwig et al. [Eur. J. Immunol. 2015. 45: 3022-3033] identify a subset of IL-17-producing γδ T cells that are capable of establishing long-lived memory in the skin of mice exposed to imiquimod in the Aldara psoriasis model. These γδ T cells uniformly express a Vγ4+Vδ4+ TCR. They produce IL-17A/F and persist in the dermis for long periods of time, also at untreated distal sites. Upon secondary challenge, experienced Vγ4+Vδ4+ cells show enhanced effector functions and mediate exacerbated secondary inflammation. These findings showcase innate γδ T-cell memory that uses a single conserved public TCR combination. Furthermore, they provide mechanistic insight to the observed psoriatic relapses in patients in response to topical treatment with imiquimod. [ABSTRACT FROM AUTHOR]

Recent studies have revealed IL-33 as a key factor in promoting antiviral T-cell responses. However, it is less clear as to how IL-33 regulates innate immunity. In this study, we infected wild-type (WT) and IL-33−/− mice with lymphocytic choriomeningitis virus and demonstrated an essential role of infection-induced IL-33 expression for robust innate IFN-γ production in the liver. We first show that IL-33 deficiency resulted in a marked reduction in the number of IFN-γ+ γδ T and NK cells, but an increase in that of IL-17+ γδ T cells at 16 h postinfection. Recombinant IL-33 (rIL-33) treatment could reverse such deficiency via increasing IFN-γ-producing γδ T and NK cells, and inhibiting IL-17+ γδ T cells. We also found that rIL-33-induced type 2 innate lymphoid cells were not involved in T-cell responses and liver injury, since the adoptive transfer of type 2 innate lymphoid cells neither affected the IFN-γ and TNF-α production in T cells, nor liver transferase levels in lymphocytic choriomeningitis virus infected mice. Interestingly, we found that while IL-33 was not required for costimulatory molecule expression, it was critical for DC proliferation and cytokine production. Together, this study highlights an essential role of IL-33 in regulating innate IFN-γ-production and DC function during viral hepatitis. [ABSTRACT FROM AUTHOR]

Background A variant in the IL-6 receptor (IL-6R) gene increases asthma risk and is predicted to decrease IL-6 classic signaling and increase IL-6 trans-signaling. This suggests that inhibition of IL-6 trans-signaling, but not classic signaling, might suppress allergic airway inflammation. Objectives We sought to determine whether IL-6 signaling contributes to (1) acute experimental asthma induced by clinically relevant allergens and (2) variation in asthma clinical phenotypes in asthmatic patients. Methods Mice were sensitized to house dust mite (HDM) or cockroach at day 0, treated with IL-6R inhibitors at day 13, and challenged with the same allergen at days 14 to 17. End points were measured 3 hours after the final challenge. IL-6 and soluble IL-6 receptor (sIL-6R) expression in induced sputum of asthmatic patients was correlated with asthma clinical phenotypes. Results Both HDM and cockroach induced a type 2/type 17 cytokine profile and mixed granulocytic inflammation in the airways. Both allergens increased IL-6 expression in the airways, but only cockroach induced sIL-6R expression. Therefore HDM challenge promoted IL-6 classic signaling but not trans-signaling; in this model treatment with anti–IL-6R did not suppress airway inflammation. In contrast, cockroach-induced inflammation involved activation of IL-6 trans-signaling and production of IL-17A by γδ T cells. Anti–IL-6R, selective blockade of sIL-6R, or γδ T-cell deficiency significantly attenuated cockroach-induced inflammation. Asthmatic patients with high airway IL-6 and sIL-6R levels were enriched for the neutrophilic and mixed granulocytic subtypes. Conclusion Experimental asthma associated with both high IL-6 and high sIL-6R levels in the airways is attenuated by treatment with IL-6R inhibitors. [ABSTRACT FROM AUTHOR]

Amphotericin B (AmB) is a commonly used antifungal drug, with well-documented effects on cellular immune responses. We determined that AmB-stimulated γδ T-cell activation and proliferation in vitro at very low concentrations. AmB also enhanced IFN-γ production by NK cells in combination with IL-18. AmB had a greater effect on IFN-γ production in cells isolated from very young animals. Although innate immunostimulatory aspects of AmB have been defined, AmB has not been extensively applied in non-fungal infection settings. Given that γδ T cells are increased and activated in Salmonella infection in cattle, we assessed the effects of AmB in protection from Salmonella enterocolitis in calves. One injection of AmB, at approximately one-tenth of the concentration used in human patients to counter fungal infection, or saline control, was delivered intravenously to calves prior to infection with Salmonella. This single injection caused no adverse effects, reduced disease symptoms from Salmonella enterocolitis and significantly reduced Salmonella bacteria shed in feces of infected animals. Our findings suggest that AmB may be an inexpensive and readily available prophylactic approach for the prevention of bacterial infection in calves. [ABSTRACT FROM AUTHOR]

Background: Lung inflammation is a major consequence of the systemic inflammatory response caused by severe sepsis. Increased migration of γδ T lymphocytes into the lungs has been previously demonstrated during experimental sepsis; however, the involvement of the γδ T cell subtype Vγ4 has not been previously described. Methods: Severe sepsis was induced by cecal ligation and puncture (CLP; 9 punctures, 21G needle) in male C57BL/ 6 mice. γδ and Vγ4 T lymphocyte depletion was performed by 3A10 and UC3-10A6 mAb i.p. administration, respectively. Lung infiltrating T lymphocytes, IL-17 production and mortality rate were evaluated. Results: Severe sepsis induced by CLP in C57BL/6 mice led to an intense lung inflammatory response, marked by the accumulation of γδ T lymphocytes (comprising the Vγ4 subtype). γδ T lymphocytes present in the lungs of CLP mice were likely to be originated from peripheral lymphoid organs and migrated towards CCL2, CCL3 and CCL5, which were highly produced in response to CLP-induced sepsis. Increased expression of CD25 by Vγ4 T lymphocytes was observed in spleen earlier than that by αβ T cells, suggesting the early activation of Vγ4 T cells. The Vγ4 T lymphocyte subset predominated among the IL-17+ cell populations present in the lungs of CLP mice (unlike Vγ1 and αβ T lymphocytes) and was strongly biased toward IL-17 rather than toward IFN-γ production. Accordingly, the in vivo administration of anti-Vγ4 mAb abrogated CLP-induced IL-17 production in mouse lungs. Furthermore, anti-Vγ4 mAb treatment accelerated mortality rate in severe septic mice, demonstrating that Vγ4 T lymphocyte play a beneficial role in host defense. Conclusions: Overall, our findings provide evidence that early-activated Vγ4 T lymphocytes are the main responsible cells for IL-17 production in inflamed lungs during the course of sepsis and delay mortality of septic mice. [ABSTRACT FROM AUTHOR]

Indolent γδ T cell lymphomas/leukemias are rare and overlap with the morphological spectrum of large granular lymphocyte (LGL) leukemia. We report an extremely rare case of CD103 γδ T LGL leukemia in a patient with celiac disease who presented with refractory diarrhea. Whether the refractory diarrhea in our patient was a manifestation of LGL leukemia itself or whether the clonal LGL expansion is a manifestation of refractory celiac disease (RCD) remains an enigma. This report highlights the diagnostic difficulties and the need of consensus in categorizing clonal CD103 lymphocytosis in patients with RCD. [ABSTRACT FROM AUTHOR]

Cancer is the major threat to human health. Traditional treatment, which combines surgery with radiotherapy, chemotherapy and other subsidiary treatments, still faces tremendous challenges to enhance the efficacy and lower the possibility of cancer recurrence. Recently immunotherapy offers a promising option for cancer treatment which evokes broad interest. Innate immune cells, in particular γδ T cells, have become the promising candidates to be adoptively transferred, because of their strong anti-tumor cytotoxicity and synergistic effect with other immune cells. This paper described the new progresses of the γδ T cells in basic research and clinical trials for cancer treatment. [ABSTRACT FROM AUTHOR]

Interactions between natural killer (NK) cells and dendritic cells (DC) affect maturation and function of both cell populations, including NK cell killing of DC (editing), which is important for controlling the quality of immune responses. We also know that antigen-stimulated Vγ2Vδ2 T cells co-stimulate NK cells via 4-1BB to enhance the killing of tumour cell lines but we do not know what regulates 4-1BB expression or whether other NK effector functions including DC killing, might also be influenced by NK-γδ T-cell cross-talk. Here we show that antigen-stimulated γδ T cells co-stimulate NK cells through inducible T-cell co-stimulator (ICOS)- ICOS ligand (ICOSL) and this signal increases NK cell killing of autologous DC. Effects of NK-γδ T-cell co-culture, which could be reproduced with soluble ICOS-Fc fusion protein, included increased CD69 and 4-1BB expression, interferon-γ, tumour necrosis factor-α, macrophage inflammatory protein-1β, I-309, RANTES and sFas ligand production, as well as elevated mRNA levels for co-stimulatory receptors OX40 (TNFRSF4) and GITR (TNFRSF18). Hence, ICOS-ICOSL co-stimulation of NK by Vγ2Vδ2 T cells had broad effects on NK phenotype and effector functions. The NK-γδ T-cell cross-talk links innate and antigen-specific lymphocyte responses in the control of cytotoxic effector function and DC killing. [ABSTRACT FROM AUTHOR]

It has been widely reported that T cells are capable of influencing osteoclast formation and bone remodelling, yet relatively little is known of the reciprocal effects of osteoclasts for affecting T cell function and/or activity. In this study we investigated the effects of human osteoclasts on the function of γδ T cells, a subset of non-CD4 + T cells implicated in a variety of inflammatory disease states. γδ T cells and CD4 + T cells were isolated from peripheral blood of healthy volunteers and were co-cultured with autologous mature osteoclasts (generated by treatment with M-CSF and RANKL) before phenotypical and functional changes in the T cell populations were assessed. Macrophages, osteoclasts, and conditioned medium derived from macrophages or osteoclasts induced activation of γδ T cells, as determined by the expression of the early activation marker CD69. TNFα was a major mediator of this stimulatory effect on γδ T cells. Consistent with this stimulatory effect, osteoclasts augmented proliferation of IL-2-stimulated γδ T cells and also supported the survival of unstimulated γδ and CD4 + T cells, although these effects required co-culture with osteoclasts. Co-culture with osteoclasts also increased the proportion of γδ T cells producing IFNγ, but did not modulate IFNγ or IL-17 production by CD4 + T cells. We provide new insights into the in vitro interactions between human γδ T cells and osteoclasts/macrophages, and demonstrate that osteoclasts or their precursors are capable of influencing γδ T function both via the release of soluble factors and also through direct cell–cell interactions. [ABSTRACT FROM AUTHOR]

Systematic evaluation of the role of γδT cells during the Schistosoma japonicum infection has not been reported, despite the fact that γδT cells contribute to many infectious diseases in innate immunity. Therefore, the aim of this study was to observe the properties of γδT cells in the liver of C57 BL/6 mice infected by S. japonicum. In this report, using immuno-fluorescent histological analysis, γδT cells were found around hepatic granulomatous. Moreover, the flow cytometry results revealed that the percentage of hepatic γδT cells increased significantly after S. japonicum infection. More interestingly, a subset of CD3−γδ TCR+ cells were found and markedly increased after infection. Furthermore, expression of activation markers ( CD25 and CD69) and cytokine profiles were detected in these hepatic CD3+γδ TCR+and CD3−γδ TCR+ cells. The significantly higher level of CD69, IL-4 and IL-17 were observed in CD3+γδ TCR+ cells after infection, suggesting that CD3+γδ TCR+ cells instead of CD3−γδ TCR+ cells might play a predominant role during the infection. Finally, our results indicated that the expression of NKG2D on CD3+γδ TCR+ cells was higher than that on CD3−γδ TCR+ cells. Collectively, γδT cells could play an important role in the liver of C57 BL/6 mouse during japonicum infection. [ABSTRACT FROM AUTHOR]

Spontaneous or medically induced reperfusion occurs in up to 70% of patients within 24 h after cerebral ischemia. Reperfusion of ischemic brain tissue can augment the inflammatory response that causes additional injury. Recently, T cells have been shown to be an essential part of the post-ischemic tissue damage, and especially IL-17 secreting T cells have been implicated in the pathogenesis of a variety of inflammatory reactions in the brain. After stroke, it seems that the innate γδ T cells are the main IL-17 producing cells and that the γδ T cell activation constitutes an early and mainly damaging immune response in stroke. Effector mechanism of γδ T cell derived IL-17 in the ischemic brain include the induction of metalloproteinases, proinflammatory cytokines and neutrophil attracting chemokines, leading to a further amplification of the detrimental inflammatory response. In this review, we will give an overview on the concepts of γδ T cells and IL-17 in stroke pathophysiology and on their potential importance for human disease conditions. [ABSTRACT FROM AUTHOR]

γδ T cells represent a major T cell population in epithelial tissues, such as skin, intestine, and lung, where they function in maintenance of the epithelium and provide a crucial first line defense against environmental and pathogenic insults. Despite their importance, the molecular mechanisms directing their activation and function have remained elusive. Epithelial-resident γδ T cells function through constant communication with neighboring cells, either via direct cell-to-cell contact or cell-to-matrix interactions. These intimate relationships allow γδ T cells to facilitate the maintenance of epithelial homeostasis, tissue repair following injury, inflammation, and protection from malignancy. Recent studies have identified a number of molecules involved in these complex interactions, under both homeostatic conditions, as well as following perturbation of these barrier tissues. These interactions are crucial to the timely production of cytokines, chemokines, growth factors, and extracellular matrix proteins for restoration of homeostasis. In this review, we discuss recent advances in understanding the mechanisms directing epithelial-T cell crosstalk and the distinct roles played by individual receptor-ligand pairs of cell surface molecules in this process. [ABSTRACT FROM AUTHOR]

γδ T cells are exported from the thymus as innate-like lymphocytes that can immediately respond to antigens. In the thymus, γδ T cells diverge into functionally distinct lineages. It is not known whether γδ T cells differentiate into regulatory cells that express Foxp3, which is an essential transcription factor for CD4 + regulatory T cells. In this study, we analyzed CD25 + immature thymocytes that give rise to both αβ and γδ thymocytes. These precursor cells have the potential to differentiate into Foxp3 + γδ T cells on a stromal cell line, TSt4-Dll1. Development of Foxp3 + γδ thymocytes in this culture was dependent on IL-2. IL-2 stimulation induced Id3, Egr1, and Egr3 expression in CD25 + immature thymocytes, suggesting that it could activate signaling molecules that are downstream of TCR signaling. The induction of Foxp3 in precursor γδ T cells suggested that IL-2 could activate the Foxp3 gene early in thymocyte development. [ABSTRACT FROM AUTHOR]

Pyrophosphorylated metabolites of isoprenoid-biosynthesis (phosphoantigens, PAgs) activate Vγ9Vδ2 T cells during infections and trigger antitumor activity. This activation depends on expression of butyrophilin 3 A1 ( BTN3A1) by antigen-presenting cells. This report defines the minimal genetic requirements for activation of Vγ9Vδ2 T cells by PAgs and mAb 20.1. We compared PAg-presentation by BTN3A1-transduced CHO hamster cells with that of CHO cells containing the complete human chromosome 6 (Chr6). BTN3A1 expression alone was sufficient for activation of Vγ9Vδ2 T-cell receptor transductants by mAb 20.1., while activation by PAgs also required the presence of Chr6. We take this finding as evidence that gene(s) on Chr6 in addition to BTN3A1 are mandatory for PAg-mediated activation of Vγ9Vδ2 T cells. This observation is important for the design of animal models for PAg-mediated immune responses and provokes speculations about the analogy between genes controlling PAg presentation and MHC-localized genes controlling peptide-antigen presentation. [ABSTRACT FROM AUTHOR]

A 70-year-old man presented with papular skin lesions and was diagnosed with Epstein- Barr virus ( EBV)-associated T-cell lymphoproliferative disorder (T- LPD). The patient showed infiltration of a large number of EBV-encoded RNA-positive T cells in the skin and lung, presence of EBV load in the peripheral blood, and expansion of clonal EBV-infected γδ T cells and CD8+ T cells in the blood and skin, as assessed by EBV-terminal repeat Southern blot, T-cell receptor polymerase chain reaction and flow cytometric analyses. In the Japanese or East Asian fatal cases of EBV-associated T/natural killer ( NK)- LPD, there are two peaks in age at death, approximately 20 years and 60 years. The former age group is associated with chronic active EBV infection ( CAEBV), and the latter group typically suffers from extranodal NK/ T-cell lymphoma. Our case is characterized not only by the unique skin and lung manifestations but also the late onset age of the disease, indicating that the skin manifestation of CAEBV can be seen even in elderly patients. [ABSTRACT FROM AUTHOR]

Inducible Treg (iTreg) cells generated from Ag-stimulated naïve CD4+ T cells in the periphery play an important role in regulating immune responses. TGF-β is a key cytokine that promotes this conversion process; however, how this process is regulated in vivo remains unclear. Here, we report that γδ T cells play a crucial role in controlling iTreg generation and suppressor function. Ag-induced iTreg generation was significantly enhanced in C57BL/6 mice in the absence of γδ T cells. Inhibition of iTreg conversion was mediated by IFN-γ produced by activated γδ T cells but not by activated CD4+ T cells. BM chimera experiments further confirmed γδ-derived IFN-γ-dependent mechanism in regulating iTreg generation in vivo. Lastly, human peripheral blood γδ T cells also interfere with iTreg conversion via IFN-γ. Our results suggest a novel function of γδ T cells in limiting the generation of iTreg cells, potentially balancing immunity and tolerance. [ABSTRACT FROM AUTHOR]

Abstract: Background: IL-17-producing CD4+ T (Th17) cells and their cytokines, IL-17A and IL-22, are deeply involved in the pathogenesis of psoriasis by stimulating epidermal keratinocytes to proliferate and to produce cytokines/chemokines and vascular endothelial growth factor (VEGF)-A. Plasmacytoid dendritic cells (pDCs), infiltrating in psoriatic lesions, are known to exacerbate the Th17-mediated pathogenesis of psoriasis. Objective: To address the initiative role of VEGF-A in the development of psoriasis and the pDC accumulation. Methods: Numerical changes and VEGF receptor 1 (VEGFR1) and VEGFR2 expressions were investigated in skin-infiltrating T cells and pDCs of K14-VEGF-A transgenic (Tg) and wild type (WT) mice. The chemotactic properties of VEGF-A for purified splenic pDCs were also evaluated by real-time chemotaxis assay. Results: By flow cytometry and immunohistochemistry, we observed that the number of dermal IL-17A+ γδ T cells, but not CD4+ T cells, was increased in VEGF-A Tg mice, suggesting that the main source of IL-17A was γδ T cells. Moreover, we identified pDCs as 440c+ cells by immunohistochemistry and as PDCA-1+B220+ cells by flow cytometry, and found that pDCs infiltrated at a higher frequency in VEGF-A Tg than WT mice. pDCs, but not γδ T cells, isolated from the skin expressed VEGFR1 and VEGFR2. Freshly isolated splenic pDCs expressed both receptors after 48-h cultivation. pDCs did not produce cytokines in response to VEGF-A, however, they had a strong velocity of chemotaxis toward VEGF-A at a comparable level to chemerin. Conclusions: These findings suggest that VEGF-A functions as not only a downstream enhancer but also an upstream initiator by chemoattracting pDCs in psoriatic lesions. [Copyright &y& Elsevier]

Highlights: [•] A novel chicken SLAMF4 specific mab is described. [•] SLAMF4 interacts with SLAMF2. [•] SLAMF4 is expressed on subpopulations of CD8+ αβ and γδ T cells. [•] SLAMF4 is found on a minor B cell population, on NK cells, monocytes and thrombocytes. [•] SLAMF4 expression levels differentiate several T cell subsets. [Copyright &y& Elsevier]

T-cell malignancies are often aggressive and associated with poor prognoses. Adoptive cell therapy has recently shown promise as a new line of therapy for patients with hematological malignancies. However, there are currently challenges in applying adoptive cell therapy to T-cell malignancies. Various approaches have been examined in preclinical and clinical studies to overcome these obstacles. This review aims to provide an overview of the recent progress on adoptive cell therapy for T-cell malignancies. The benefits and drawbacks of different types of adoptive cell therapy are discussed. The potential advantages and current applications of innate immune cell-based adoptive cell therapy for T cell malignancies are emphasized.

Gamma delta (γδ) T cells are highly enriched in mucosal barrier sites including intestinal tissues where microbial infections and tumors often originate in mammals. Human γδ T cells recognize stress antigens and microbial signals via their T cell receptor (TCR), natural killer (NK) receptors, and pattern recognition receptors. However, little is known about antigens or ligands capable of stimulating chicken γδ T cells. The results of the present study demonstrated that polyinosinic-polycytidylic acid (poly(I:C)), a Toll-like receptor (TLR)3 ligand, significantly induced upregulation of CD8α molecules on circulating and lung γδ T cells. Moreover, poly(I:C) stimulation induced interferon (IFN)-γ production from splenic and lung CD8α+ γδ T cells while Cytosine-phosphate-Guanine oligodeoxynucleotides (CpG-ODN) 2007, a TLR21 ligand, stimulation induced IFN-γ production by circulating γδ T cells. Neither poly(I:C) nor CpG-ODN 2007 stimulation elicited degranulation of γδ T cells. Additionally, the results revealed that CpG-ODN 2007 induced IFN-γ production from TCR-stimulated γδ T cells sorted from spleen. In our experiments, isopentenyl pyrophosphate (IPP), 4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), or zoledronate (Zol) stimulation did not induce IFN-γ production or degranulation in γδ T cells. Taken together, a combination of CpG-ODN 2007 and anti-CD3ε monoclonal antibodies (mAbs) can stimulate chicken γδ T cells and induce production of IFN-γ by these cells while IFN-γ production by γδ T cells induced by stimulation of poly(I:C) needs signals from other cells. These results suggest that chicken γδ T cells can sense invading pathogens via TLRs and produce IFN-γ as a first line of defense. • poly(I:C) stimulation upregulated CD8α molecules on chicken γδ T cells derived from PBMCs and lungs. • poly(I:C) induced IFN-γ production by spleen and lung γδ T cells, but this induction needs other signals from non γδ T cells. • CpG-ODN 2007 induced IFN-γ secretion by TCR co-stimulated γδ T cells. • Degranulation by chicken γδ T cells need other signals rather than those mediated by TLR3 and TLR21. • Phosphoantigen stimulation elicited neither IFN-γ production nor degranulation by chicken γδ T cells. [ABSTRACT FROM AUTHOR]

Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation, and inflammatory processes play a major role in myocardial IR injury. Long pentraxin-3 (PTX3) is a member of a phylogenetically conserved group of acute-phase reactants that are involved in inflammation and innate immunity. In our study, hearts of C57Bl/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipient. We found that both mRNA and protein levels of PTX3 were increased following myocardial IR injury; neutralizing antibody against PTX3 aggravated cardiomyocyte apoptosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by exogenous PTX3 administration and increased by PTX3 neutralization in comparison with control. Cardiac output at 60 mmHg of afterload pressure was also increased in hearts with exogenous PTX3 administration and decreased with PTX3 neutralization (PTX3: 58.4 ± 7.4 ml/min; Control: 24.5 ± 3.8 ml/min; Anti-PTX3: 11.6 ± 1.7 ml/min; P < 0.05). Furthermore, PTX3 restricted expansion of γδ T cell that was the major source of IL-17A and down-regulated expression of IL-23 and IL-17A. In conclusion, PTX3 played a protective role in cardiomyocyte IR injury. PTX3 ameliorated cardiomyocyte apoptosis and infiltration of neutrophil and macrophage and then improved hemodynamic performance. This was associated with restricted γδ T-cell expansion and decreased IL-23/IL-17A expression. [ABSTRACT FROM AUTHOR]

Background To investigate the characteristics of γδ T cells as well as the Vδ1+ and Vδ2+ subsets in the peripheral blood in liver allograft recipients. Methods Sixty-three liver transplant recipients were enrolled in this study: 26 cases with acute allograft rejection (Gr-AR), and 37 cases with stable allograft liver function (Gr-SF). The frequencies of γδ T cells, the Vδ1+ and Vδ2+ subsets, and interleukin (IL)-10-producing Vδ1+ γδ T cells in the peripheral blood were analyzed by flow cytometry. The relationship between liver function parameters and the Vδ1+/Vδ2+ ratio was analyzed. Results The frequency of the Vδ1+ subset and the Vδ1+/Vδ2+ ratio in Gr-SF was significantly higher than that in Gr-AR; in contrast, the frequency of the Vδ2+ subset in Gr-SF was markedly lower than that in Gr-AR. In addition, there was no significant difference in the frequency of γδ T cells between the Gr-AR and Gr-SF groups. Moreover, there was a significant negative correlation between the Vδ1+/Vδ2+ ratio with the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in Gr-AR. Conclusions Vδ1+ γδ T cells may have a potential role in maintaining stable graft liver function, and Vδ2+ γδ T cells may be associated with liver allograft rejection. The Vδ1+/Vδ2+ ratio could serve as a prognostic marker for acute rejection after liver transplantation. [ABSTRACT FROM AUTHOR]

Abstract: γδ T cells play important roles in innate immunity against tumors and infections. Inhibitory effect of dihydroartemisinin on growth of cancer cells has been found in recent years. In this study, we investigated the effect of dihydroartemisinin on human γδ T cell proliferation by MTT assay and killing activity against pancreatic cancer cells SW1990, BxPC-3 and PANC-1 by LDH release assay in vitro. Intracellular molecule alterations were verified by flow cytometry. The results suggested that appropriate concentration of dihydroartemisinin favored the expansion of γδ T cells and enhanced γδ T cell mediated killing activity against pancreatic cancer cells. Up-regulation of intracellular perforin, granzyme B expression and IFN-γ production may be the important mechanism of dihydroartemisinin on increased antitumor activity of γδ T cells. [Copyright &y& Elsevier]

Abstract: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The etiology of MS is not well understood, but it is believed that myelin-specific CD4+ T cells play a central role in initiating and orchestrating CNS inflammation. In this scenario, CD4+ T cells, activated in the periphery, infiltrate the CNS, where, by secreting cytokines and chemokines, they start an inflammatory cascade. Given the central role of CD4+ T cells in CNS autoimmunity, they have been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the late 1980s, CD4+ T cells, based on their cytokine production, were divided into two helper lineages, Th1 and Th2 cells. It was postulated that Th1 cells, which produce IFN-γ, mediate inflammation of the CNS in MS/EAE, while Th2 cells, which produce IL-4, have a beneficial effect in disease, because of their antagonistic effect on Th1 cells. The Th1/Th2 paradigm remained the prevailing view of MS/EAE pathogenesis until 2005, when a new lineage, Th17, was discovered. In a relatively short period of time it became apparent that Th17 cells, named after their hallmark cytokine, IL-17A, play a crucial role in many inflammatory diseases, including EAE, and likely in MS as well. The Th17 paradigm developed rapidly, initiating the debate of whether Th1 cells contribute to EAE/MS pathogenesis at all, or if they might even have a protective role due to their antagonistic effects on Th17 cells. Numerous findings support the view that Th17 cells play an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease. Hence, the current view on the role of Th cells in MS/EAE pathogenesis can be called the Th17/Th1 paradigm. It is certain that Th17 cells will continue to be the focus of intense investigation aimed at elucidating the pathogenesis of CNS autoimmunity. [Copyright &y& Elsevier]

Objective To evaluate the state of oral tolerance and its therapeutic role in mice with dextran sulfate sodium ( DSS)-induced colitis. Methods Delayed-type hypersensitivity ( DTH) was determined 7 and 14 days after DSS-induced colitis and control mice. Disease activity index ( DAI) score and colonic histopathological score were measured 7 days after colonic extracted protein ( CEP) or bovine serum albumin ( BSA) (control) was administrated, with the evaluation of Th1-Th2 balance in the spleen, Peyer's patch and γδ T cells in intraepithelial lymphocytes and lamina proper lymphocytes in the intestine. Results After fed with 250 μg ovalbumin oral tolerance was induced in 7 days in both DSS-induced colitis and control mice, while oral tolerance persisted in the control mice but vanished in DSS-induced colitis 14 days after ovalbumin challenge. DAI and colonic histopathological scores were decreased significantly after the ingestion of CEP (controlled by BSA) in DSS-induced colitis with significant reduction of Th1 and the ratio of Th1 to Th2 in Peyer's patch as well as the γδ T cells in lamina proper lymphocytes in the intestine. No significant difference in Th1-Th2 balance in the spleen and γδ T cells in intraepithelial lymphocytes in the intestine were observed. Conclusions There is a defect in oral tolerance at day 7 in DSS-induced colitis. If taken orally, CEP may have a protective role in DSS-induced colitis, which may be related to the deflection from Th1 to Th2 in Peyer's patch and the reduction of γδ T cells in lamina proper lymphocytes in the intestine. [ABSTRACT FROM AUTHOR]

T cells employ a cell surface heterodimeric molecule, the T cell receptor (TCR), to recognize specific antigens (Ags) presented by major histocompatibility complex (MHC) molecules and carry out adaptive immune responses. Most T cells possess a TCR with an α and a β chain. However, a TCR constituted by a γ and a δ chain has been described, defining a novel subset of T cells. γδ TCRs specific for a wide variety of ligands, including bacterial phosphoantigens, nonclassical MHC-I molecules and unprocessed proteins, have been found, greatly expanding the horizons of T cell immune recognition. This review aims to provide background in γδ T cell history and function in mouse and man, as well as to provide a critical view of some of the latest developments on this still enigmatic class of immune cells. [ABSTRACT FROM AUTHOR]

The specification of the αβ/γδ lineage and the maturation of medullary thymic epithelial cells (mTECs) coordinate central tolerance to self-antigens. However, the mechanisms underlying this biological process remain poorly clarified. Here, we report that dual-stage loss of TOX in thymocytes hierarchically impaired mTEC maturation, promoted thymic IL-17A-producing γδ T-cell (Tγδ17) lineage commitment, and led to the development of fatal autoimmune hepatitis (AIH) via different mechanisms. Transfer of γδ T cells from TOX-deficient mice reproduced AIH. TOX interacted with and stabilized the TCF1 protein to maintain the balance of γδ T-cell development in thymic progenitors, and overexpression of TCF1 normalized αβ/γδ lineage specification and activation. In addition, TOX expression was downregulated in γδ T cells from AIH patients and was inversely correlated with the AIH diagnostic score. Our findings suggest multifaceted roles of TOX in autoimmune control involving mTEC and Tγδ17 development and provide a potential diagnostic marker for AIH., (© 2022. The Author(s), under exclusive licence to CSI and USTC.)

Idiopathic pulmonary fibrosis is a chronic intractable lung disease, leading to respiratory failure and death. Although anti-fibrotic agents delay disease progression, they are not considered curative treatments, and alternative modalities have attracted attention. We examined the effect of human γδ T cells on collagen type I in lung fibroblasts. Collagen type I was markedly reduced in a γδ T cell number-dependent manner following treatment with γδ T cells expanded with tetrakis-pivaloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2. Collagen type I levels remained unchanged on addition of γδ T cells to the culture system through a trans-well culture membrane, suggesting that cell-cell contact is essential for reducing its levels in lung fibroblasts. Re-stimulating γδ T cells with (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) reduced collagen type I levels without cell-cell contact, indicating the existence of HMBPP-induced soluble anti-fibrotic factors in γδ T cells. Adding anti-interferon-γ (IFN-γ)-neutralizing mAb restored collagen type I levels, demonstrating that human γδ T cell-derived IFN-γ reduces collagen type I levels. Conversely, interleukin-18 augmented γδ T cell-induced suppression of collagen type I. Therefore, human γδ T cells reduce collagen levels in lung fibroblasts via two distinct mechanisms; adoptive γδ T cell transfer is potentially a new therapeutic candidate.

The authors discuss the controversy on the relative contributions of the natural killer receptors (NKRs) and γδ T-cell receptor (TCR) to tumor-cell which targets by γδ T cells. They mention that key characteristic shared by the two subsets of lymphocyte is the expression of receptors encoded with germline depicted in natural killer (NK) cells. They state that γδ cells depend on the TCRγδ for the perception of pathogen-related molecular patterns.

The aim of this study was to explore whether desensitization to the occurrence of the acute-phase response (APR) in patients previously treated with amino-bisphosphonates (N-BPs) is due to a long-lasting reduction in the number of circulating γδ T cells. Circulating lymphocyte subpopulation counts were obtained from 63 patients with postmenopausal or senile osteoporosis at baseline and after 2 days and 12 months of the first intravenous (IV) 5 mg zoledronic acid (ZOL) infusion. At baseline both the proportion and absolute number of circulating γδ T cells were significantly higher in patients who had never used N-BPs vs. previous users, either oral or IV. A typical APR was observed in none of the patients given IV ZOL a year earlier, in 6 (22 %) of the patients previously treated with oral N-BPs, and in 13 (57 %) of the patients naive to any N-BP treatment. In patients naive to N-BPs, a significant reduction in both total lymphocytes and their subsets was observed 2 days after ZOL infusion; all these changes returned to baseline values 1 year later with the exception of γδ T cells, which remained significantly lower in terms of both proportion and absolute number. These results indicate for the first time that both IV and oral N-BP treatments are associated with a long-lasting decrease in circulating γδ T cells, and this may explain the lower incidence of APR in patients previously exposed to N-BPs. Other clinical implications of this sustained effect of N-BPs on immune-regulatory cells might be important. [ABSTRACT FROM AUTHOR]

Abstract: Various subsets of T-cell receptor (TCR) γδ+ T cells expressing distinct TCR-Vγ chains are found in many different anatomical locations. These TCR γδ+ T cells perform multiple functions as an essential part of the immune system. In particular, protection against malaria infection by TCR γδ+ T cells is of special interest. In the present study, we confirmed that the Vγ7+ γδ T cells, which are an unconventional subset usually localized within the intestine, are recruited to the liver and spleen at the late stage of malaria infection, and contribute to protection against malaria infection via a multifunctional approach in apoptosis inhibitor-deficient mice. [Copyright &y& Elsevier]

We previously showed that formation of pulmonary granulomas in mice in response to a mycobacterial glycolipid, trehalose 6,6′-dimycolate (TDM) is due to the action of TNF-α and not of IFN-γ. However, the mechanisms of formation and maintenance of pulmonary granulomas are not yet clear. The purpose of the present study is to evaluate the mechanisms of granuloma formation by TDM at the early phase. Histological analysis showed that inflammatory cells infiltrated the murine pulmonary interstitium on day 2 after an intravenous injection with TDM as a w/o/w emulsion. Clear granuloma formation was observed on day 7 after the injection. The mRNA expression of IL-17, IFN-γ and macrophage inflammatory protein 2 was found in lung mononuclear cells at the day after TDM injection. The major IL-17-producing cells were T-cell receptor (TCR) γδ T cells expressing Vγ6. In mice depleted of γδ T cells by treatment with anti-TCR γδ monoclonal antibody, the number of TDM-induced granuloma was decreased, but the size of granuloma was not affected. Our results suggest that the mycobacterial glycolipid TDM causes activation of IL-17-producing TCR γδ T cells and stimulates chemotaxis of inflammatory cells including neutrophils in to lung. [ABSTRACT FROM AUTHOR]