Understanding Of Γδ Research Articles

CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.

γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1-5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells4-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6-8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.

Age-Related Changes in Female Murine Reproductive Mucosa with respect to γδ T Cell Presence.

Many studies have demonstrated a general decline and dysregulation in immune functions with age. It is not clear, however, how the aging affects the immune surveillance of the female reproductive tract (FRT) by γδ T cells, a unique population of T lymphocytes that was shown to regulate homeostasis of epithelial barriers. First, we analyzed γδ T cell presence in FRT in young (2 months) and old (18 months) wild-type (WT) C57BL/6 mice. We did not detect any changes in γδ T cell number nor distribution in the vaginas between the age groups, while in uteri, there was a twofold increase in γδ T cell number in aged mice. To check if γδ T lymphocytes regulate a metabolic and immune status of aging vaginal tissue, we compared the expression of 84 aging-associated genes in young and old WT and γδ T-cell-deficient (Tcrd -/-) mice. We discovered that only the Ltf (lactotransferrin) gene was downregulated in old Tcrd -/- mice. In both mouse strains, we found similar age-dependent changes in cytokine production upon vaginal inflammation due to Toll-like receptor 9 (TLR9) stimulation with CpG. With age in the vaginas, IL-1α and IL-17A levels increased while IL-6, IL-10, MCP-1, and IFNγ levels were diminished in response to CpG. Similar trends were observed in uteri. Interestingly, under the inflammatory state, the lack of γδ T cells in young individuals enhanced MCP-1 production in the vagina and decreased MCP-1 level in the uterus in old females. Our gene expression data point to an antimicrobial role of γδ T lymphocytes. The profile of secreted inflammatory cytokines shifted during aging toward the proinflammatory type, and γδ T cells played a modest fine-tuning role in immunoregulation in aged FRT. We believe this work expands our understanding of γδ T cell functions and the inflammaging in the murine reproductive epithelia.

Gamma delta T-cell reconstitution after allogeneic HCT: A platform for cell therapy.

Allogeneic Hematopoietic stem cell transplantation (allo-HCT) is a curative platform for several hematological diseases. Despite its therapeutic benefits, the profound immunodeficiency associated with the transplant procedure remains a major challenge that renders patients vulnerable to several complications. Today, It is well established that a rapid and efficient immune reconstitution, particularly of the T cell compartment is pivotal to both a short-term and a long-term favorable outcome. T cells expressing a TCR heterodimer comprised of gamma (γ) and delta (δ) chains have received particular attention in allo-HCT setting, as a large body of evidence has indicated that γδ T cells can exert favorable potent anti-tumor effects without inducing severe graft versus host disease (GVHD). However, despite their potential role in allo-HCT, studies investigating their detailed reconstitution in patients after allo-HCT are scarce. In this review we aim to shed lights on the current literature and understanding of γδ T cell reconstitution kinetics as well as the different transplant-related factors that may influence γδ reconstitution in allo-HCT. Furthermore, we will present data from available reports supporting a role of γδ cells and their subsets in patient outcome. Finally, we discuss the current and future strategies to develop γδ cell-based therapies to exploit the full immunotherapeutic potential of γδ cells in HCT setting.

Genome-wide CRISPR screens reveal metabolic and transcriptional regulation of BTN3A and cancer susceptibility to Vγ9Vδ2 T cell targeting

Abstract γδ T cells are potent anti-cancer effectors with potential to target tumors broadly, independent of neoantigens or HLA-background. γδ T cells can sense conserved cell stress signals prevalent in transformed cells, although the mechanisms governing how γδ T cells sense and kill stressed target cells remain poorly characterized. Vγ9Vδ2 T cells – the most abundant subset of human γδ T cells – recognize a protein complex containing butyrophilin 3A1 (BTN3A1), a ubiquitously expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumor cells. Here we performed genome-wide CRISPR screens in target cancer cells to identify pathways that regulate: (1) γδ T cell activity with a functional co-culture killing screen, and (2) BTN3A1 cell surface expression in a phenotypic screen. Multilayered regulation of BTN3A1 expression was uncovered: transcriptional regulation (IRF1, CTBP1, ZNF217, RUNX1), intracellular trafficking, sialylation, oxidative phosphorylation (OXPHOS), purine metabolism, and other metabolic pathways. Consistent with these results, we found upregulated BTN3A1 on cells undergoing an energy crisis due to glucose deprivation, glycolysis inhibition, or OXPHOS inhibition. Furthermore, we discovered that this BTN3A1 upregulation was induced by activation of the AMP-activated protein kinase (AMPK). Also, CRISPR screen-derived gene expression signatures correlated with higher survival in low-grade glioma patients whose tumors had high Vγ9Vδ2 T cell infiltration. Uncovering this AMPK-dependent mechanism of metabolic stress-induced ligand activation deepens our understanding of γδ T cell stress surveillance and suggests new avenues to enhance γδ T cell anti-cancer activity. M.R.M. is a Cancer Research Institute (CRI) Irvington Fellow supported by CRI and was funded by the Human Vaccines Project Michelson Prize for Human Immunology.

Novel insights based on the plasticity of γδ T cells in the tumor microenvironment

γδ T cells express unique T cell receptor (TCR) γ and TCR δ chains, with structural and functional heterogeneity. Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. γδ T cells recruited into the tumor microenvironment can act as effector cells to mediate cancer immune surveillance. Their advantage lies in the ability to perceive tumors with a low mutation load, thus establishing the first line of defense against pathogens. Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. However, the clinical application of tumor-infiltrating γδ T cells has certain limitations. First, γδ T cells exposed to complicated cytokine networks are potentially affected by multiple inhibitory mechanisms. Additionally, these cells show highly flexible and dynamic plasticity and are extremely easily polarized into regulatory phenotypes. This review further emphasizes the diversified cross-talk between γδ T cells and other immune cells. Effective immunity of the body is often manifested by counterbalance under mutual restriction. Therefore, an in-depth understanding of γδ T cells that play conflicting roles in the tumor microenvironment is necessary. These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. According to current challenges, there is a need to explore innovative immunotherapies, maximize the tumor-killing efficacy of γδ T cells, and attenuate or eliminate tumor immunosuppression. It is hoped that the host immune status can be accurately predicted and gradually advance γδ T cell precise individualized medicine.

The Mysterious Actor-γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL).

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults. It is the clonal expansion of B cells expressing CD19 and CD5. Despite significant progress in treatment, CLL is still incurable. γδ T cells comprise an important subset of the cytotoxic T cells. Although γδ T cells in CLL are dysfunctional, they still can possibly be used for immunotherapy. The current paper reviews our understanding of γδ T lymphocytes in CLL.

Rapid activation and expansion of peripheral gammadelta (γδ) T cells in SARS-CoV-2-infected nonhuman primates following aerosol exposure

Abstract Infection with SARS-CoV-2, the novel coronavirus responsible for the current COVID-19 pandemic, results in a wide range of pathologies from asymptomatic/mild outcome to fulminant pneumonia and progression to acute respiratory distress syndrome (ARDS). The cellular mechanisms underlying this spectrum of disease remain unknown. We investigated the dynamic changes in frequency and activation status of peripheral innate lymphocyte subsets in two different species of nonhuman primates. Cohorts of Rhesus macaques (n=8) and African Green monkeys (n=8) were infected with SARS-CoV-2 either by small particle or mucosal (IN/IT) route. Flow cytometric analysis of PBMCs revealed a rapid and significant increase in circulating γδ T cell frequencies and activation at d1 postexposure across all animals inoculated by aerosol, which was correlative with peak viral loads in lung lavage and Vδ2 T cell frequencies. Further, elevated GranzymeB expression in both Vδ1 and Vδ2 subsets of γδ T cells was suggestive of increased cytotoxic function in early infection. In contrast, mucosally-infected animals showed little change in circulating γδ T cell frequencies from d1 through d7 post-infection, nor were there remarkable differences in early MAIT and NK cell frequencies. Collectively, these data suggest γδ T cells may be early responders to deep lung SARS-CoV-2 infection and the kinetics and quality of immune response are dependent upon route of exposure despite resulting in similar peak viral loads from infection. Further understanding of γδ T cell functions within the pulmonary compartment during SARS-CoV-2-driven acute inflammation may reveal tractable therapeutic approaches to further mitigate ARDS-like responses in COVID-19 patients.

Abstract PO013: The mechanism of γδ T cell-mediated antitumor immunity in Glioblasotma multiforme

Abstract Glioblastoma multiforme (GBM) is a highly malignant cancer with one of the highest mortality rates. The average survival is less than 2 years after diagnosis even with current therapies, which include chemotherapy and radiation. Furthermore, GBM has shown severe resistance to immunotherapies such as immune checkpoint blockade, which mainly target CD8 T cells. Recently, several studies showed that γδ T cells can be an alternative target of immunotherapy. Unlike conventional ab T cells, γδ T cells recognize stress-induced surface antigens such as NKG2D ligands and phosphoantigens. Because GBM cells highly express NKG2D ligands, γδ T cells could be good target for immunotherapy. However, a basic understanding of γδ T cell-mediated antitumor immunity is lacking. Using single-cell transcriptomic analysis, we analyzed the characteristics of GBM-infiltrating γδ T cells. Because γδ T cells were highly suppressed by the poorly oxygenated microenvironment of brain tumors, we inhibited tumor cell respiration using metformin, a drug used for type 2 diabetes, and found that this sufficiently reinvigorated γδ T cells. Reinvigorated γδ T cells had enhanced expression of NKG2D and multiple cytokines. In conclusion, this study highlights the importance of γδ T cells in GBM and the potential for new druggable pathways through reinvigoration of γδ T cells. Citation Format: Jang Hyun Park, Heung Kyu Lee. The mechanism of γδ T cell-mediated antitumor immunity in Glioblasotma multiforme [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO013.

Deciphering the regulatory landscape of fetal and adult γδ T‐cell development at single‐cell resolution

γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high‐resolution map of γδ T‐cell differentiation from the fetal and adult thymus using single‐cell RNA sequencing. We reveal novel sub‐types of immature and mature γδ T cells and identify an unpolarized thymic population which is expanded in the blood and lymph nodes. Our detailed comparative analysis reveals remarkable similarities between the gene networks active during fetal and adult γδ T‐cell differentiation. By performing a combined single‐cell analysis of Sox13, Maf, and Rorc knockout mice, we demonstrate sequential activation of these factors during IL‐17‐producing γδ T‐cell (γδT17) differentiation. These findings substantially expand our understanding of γδ T‐cell ontogeny in fetal and adult life. Our experimental and computational strategy provides a blueprint for comparing immune cell differentiation across developmental stages.

Pathogen-elicited memory γδ T cells express a broadly reactive canonical TCR or a pathogen-specific non-canonical TCR

Abstract γδ T cells are critical sentinels protecting barrier surfaces against pathogens. However, our understanding of γδ T cell specificity remains limited. We previously identified a resident memory Vγ4Vδ1 T cell population elicited by foodborne Listeria monocytogenes (Lm) infection. Analysis of the CDR3δ sequences revealed that a large subset of non-canonical clones expanded during primary Lm infection, contracted during memory homeostasis and recalled after secondary Lm infection suggesting antigenic-specificity may be involved in this response. However, most of the response was elicited by cells bearing a canonical Vδ1 TCR suggesting that many Lm-elicited cells may not be Lm-specific. Indeed, stimulation of mesenteric lymph node cells from Lm-immune mice with diverse pathogens induced a functional response by Lm-elicited memory γδ T cells. Similarly, induction of Salmonella colitis (STm-colitis) in Lm-immune mice resulted in a TCR-dependent γδ T cell recall-like response, demonstrating that the majority of these memory cells respond to heterologous infection. Interestingly, most of the non-canonical γδ T cell clones that responded to Lm infection did not expand in response to STm-colitis suggesting some level of specificity is imparted by the priming pathogen. Importantly, other enteropathogens triggered a recall-like response of Lm-elicited memory γδ T cells. Adaptive γδ T cells were also generated after foodborne infection of germ-free mice and in response to diverse bacterial infections of SPF mice, indicating that this population can be induced by a broad range of disseminating pathogens and may provide a broad target for universal mucosal vaccines of the gut.

Abstract A22: A mechanism of γδ T cell-mediated antitumor immunity against brain cancer

Abstract Glioblastoma multiforme (GBM) is one of the less survivable and most malignant brain tumors. The average survival period is less than 2 years despite multiple therapies including chemotherapy and radiation. Furthermore, GBM showed severe resistance against immunotherapies such as immune checkpoint blockade mainly targeting CD8 T cells (1). Recently, several studies showed that γδ T cells can be an alternative target of immunotherapy. Unlike conventional T cells, γδ T cells recognize stress-induced surface antigens such as NKG2D-ligands and phosphor-antigens (2). Because GBM cells highly express NKG2D-ligands, γδ T cells could be proper targets for immunotherapy. However, a basic understanding of γδ T cell-mediated antitumor immunity remains unclear. Using single-cell transcriptomic analysis, we analyzed the characteristics of GBM-infiltrating γδ T cells. γδ T cells are highly suppressed by oxygen tension of tumor microenvironment in the brain tumor. We inhibited respiration of tumor cells by metformin, which is the drug for type 2 diabetes. Inhibition of tumor cell respiration sufficiently reinvigorated γδ T cells. Reinvigorated γδ T cells highly expressed NKG2D and multiple cytokines. In conclusion, this study highlights the importance of γδ T cells and the druggable pathways through reinvigoration of γδ T cells. Citation Format: Jang Hyun Park, Heung Kyu Lee. A mechanism of γδ T cell-mediated antitumor immunity against brain cancer [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A22.

The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases.

Autoimmune rheumatic diseases (ARDs), affecting ~1–1.5% of all humans, are associated with considerable life long morbidity and early mortality. Early studies in the 1990s showed numerical changes of the recently discovered γδ T cells in the peripheral blood and in affected tissues of patients with a variety of ARDs, kindling interest in their role in the immuno-pathogenesis of these chronic inflammatory conditions. Indeed, later studies applied rapid developments in the understanding of γδ T cell biology, including antigens recognized by γδ T cells, their developmental programs, states of activation, and cytokine production profiles, to analyze their contribution to the pathological immune response in these disorders. Here we review the published studies addressing the role of γδ T in the major autoimmune rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematosus and scleroderma, and animal models thereof. Due to their unique properties spanning adaptive and innate immune functions, the ever deeper understanding of this unique T cell population is shedding new light on the pathogenesis of, while potentially enabling new therapeutic approaches to, these diseases.

γδ T cells in rheumatic diseases: from fundamental mechanisms to autoimmunity.

The innate and adaptive arms of the immune system tightly regulate immune responses in order to maintain homeostasis and host defense. The interaction between those two systems is critical in the activation and suppression of immune responses which if unchecked may lead to chronic inflammation and autoimmunity. γδ T cells are non-conventional lymphocytes, which express T cell receptor (TCR) γδ chains on their surface and straddle between innate and adaptive immunity. Recent advances in of γδ T cell biology have allowed us to expand our understanding of γδ T cell in the dysregulation of immune responses and the development of autoimmune diseases. In this review, we summarize current knowledge on γδ T cells and their roles in skin and joint inflammation as commonly observed in rheumatic diseases.

Characterization of γδ T Cell Effector/Memory Subsets Based on CD27 and CD45R Expression in Response to Mycobacterium bovis Infection.

Tuberculosis (TB) remains a leading cause of death from infectious diseases worldwide. Mycobacterium bovis is the causative agent of bovine TB and zoonotic TB infection. γδ T cells are known to participate in the immune control of mycobacterial infections. Data in human and nonhuman primates suggest that mycobacterial infection regulates memory/effector phenotype and adaptive immune functions of γδ T cells. To date, the impact of M. bovis infection on bovine γδ T cells and their effector and memory differentiation remains unknown. In this study, we show that circulating γδ T cells from M. bovis-infected cattle can be differentiated based on the expression of CD27, which is indicative of their capacity to respond to virulent M. bovis infection: CD27+ γδ T cells proliferated in response to M. bovis Ag and, thus, may comprise the adaptive γδ T cell compartment in cattle. We further show that bovine M. bovis-specific γδ T cells express surface markers characteristic of central memory T cells (CD45R-CD27+CD62Lhi) and that M. bovis-specific CD4 and γδ T cells both upregulate the expression of the tissue-homing receptors CXCR3 and CCR5 during infection. Our studies contribute significantly to our understanding of γδ T cell differentiation during TB infection and provide important insights into the link between phenotypic and functional subsets in the bovine. Accurate characterization of γδ T cell effector and memory-like responses induced during mycobacterial infection will contribute to improved strategies for harnessing the γδ T cell response in protection against TB for humans and animals.

Apoptosis Induced via Gamma Delta T Cell Antigen Receptor "Blocking" Antibodies: A Cautionary Tale.

Mechanistic studies contribute greatly to our understanding of γδ T cell (γδTc) biology, aiding development of these cells as immunotherapeutic agents. The antibody blocking assay is an accepted method to determine the receptors involved in γδTc killing of tumor targets. Effectors and/or targets are preincubated with microgram quantities of monoclonal antibodies (mAb), often described by commercial sources to be useful for blocking assays. We and others have used such assays extensively in the past, correlating decreases in cytotoxicity against specific targets with involvement of the blocked receptor(s). However, we wondered whether other mechanisms might be at play beyond cytotoxicity inhibition. Indeed, administration of certain “blocking” mAb to the γδ T cell antigen receptor (γδTCR) induced γδTc death. Upon further investigation, we discovered that γδTc underwent apoptosis triggered by incubation with mAb to the γδTCR. This effect was specific, as no apoptosis was observed when αβ T cells (αβTc) were incubated with these mAb. Apoptosis was further potentiated by the presence of interleukin (IL)-2, often included in cytotoxicity assays; however, exogenous interleukin-2 (IL-2) did not contribute significantly to γδTc cytotoxicity against breast cancer cell lines. Here, we have investigated the usefulness of four mAb for use in blocking assays by assessing blocking properties in conjunction with their propensity to induce apoptosis in cultured primary human γδTc. We found that the 5A6.E9 clone was usually a better alternative to the commonly used B1 (or B1.1) and 11F2 clones; however, some variability in susceptibility to apoptosis induction was observed among donor cultures. Thus, viability assessment of primary effector cells treated with mAb alone should be undertaken in parallel with cytotoxicity assays employing blocking antibodies, to account for cytotoxicity reduction caused by effector cell death. Previous findings should be reassessed in this light.

Specific Recognition of Mycobacterial Protein and Peptide Antigens by γδ T Cell Subsets following Infection with VirulentMycobacterium bovis

Promoting effective immunity to Mycobacterium bovis infection is a challenge that is of interest to the fields of human and animal medicine alike. We report that γδ T cells from virulent M. bovis-infected cattle respond specifically and directly to complex, protein, and nonprotein mycobacterial Ags. Importantly, to our knowledge, we demonstrate for the first time that bovine γδ T cells specifically recognize peptide Ags derived from the mycobacterial protein complex ESAT6:CFP10 and that this recognition requires direct contact with APCs and signaling through the T cell Ag receptor but is independent of MHC class I or II. Furthermore, we show that M. bovis infection in cattle induces robust IL-17A protein responses. Interestingly, in contrast to results from mice, bovine CD4 T cells, and not γδ T cells, are the predominant source of this critical proinflammatory mediator. Bovine γδ T cells are divided into subsets based upon their expression of Workshop Cluster 1 (WC1), and we demonstrate that the M. bovis-specific γδ T cell response is composed of a heterogeneous mix of WC1-expressing populations, with the serologically defined WC1.1(+) and WC1.2(+) subsets responding in vitro to mycobacterial Ags and accumulating in the lesions of M. bovis-infected animals. The results described in this article enhance our understanding of γδ T cell biology and, because virulent M. bovis infection of cattle represents an excellent model of tuberculosis in humans, contribute to our overall understanding of the role of γδ T cells in the mycobacterial-specific immune response.

The role of gamma delta T cells in immunity to Mycobacterium bovis infection in cattle

Accumulating evidence suggests that γδ T cells play a critical role in the early response to Mycobacterium bovis and may be key in bridging innate and adaptive immunity following infection. In vitro, γδ T cells proliferate and produce robust amounts of IFNγ in response to complex, protein and non-protein mycobacterial antigens including M. bovis purified protein derivative (PPD), heat shock proteins and cell wall components such as mycolylarabinogalactan peptidoglycan (mAGP). Vaccination with Bacille Calumette-Guerin (BCG), as well as infection with virulent M. bovis, induces an increase in the frequency and activation of WC1+ γδ T cells circulating in the blood. Gamma delta T cells are rapidly recruited to the lungs and draining lymph nodes following BCG vaccination, and accumulate in developing lesions early following M. bovis infection. In Severe Combined Immuno-deficient (SCID)-bo mice, depletion of γδ T cells prior to M. bovis infection results in impaired granuloma formation, suggesting a role for γδ T cells in immune cell recruitment and lesion development. In vivo depletion of WC1+ γδ T cells from calves prior to M. bovis infection results in significantly reduced levels of M. bovis specific IgG2 and IFNγ, and increased IL-4 production compared to non-depleted control animals, suggesting that γδ T cells may also play a role in shaping the character of the adaptive M. bovis specific immune response. Whereas it is clear that γδ T cells are responding during M. bovis infection, much remains to be understood about their function in vivo and their ability to shape the innate and adaptive immune responses. This review focuses on recent advances in our understanding of γδ T cell biology with a particular emphasis on the immune response of γδ T cells in cattle during M. bovis infection.

Comparative Gamma Delta T Cell Immunology: A Focus on Mycobacterial Disease in Cattle

A theme among many pathogenic mycobacterial species affecting both humans and animals is a prolonged asymptomatic or latent period that can last years to decades. The mechanisms that favor progression to active disease are not well understood. Pathogen containment is often associated with an effective cell-mediated or T-helper 1 immune profile. With certain pathogenic mycobacteria, such as Mycobacterium avium subspecies paratuberculosis, a shift to active clinical disease is associated with loss of T-helper 1 immunity and development of an ineffective humoral or T-helper 2 immune response. Recently γδ T cells have been shown to play a role early in mycobacterial infections and have been hypothesized to influence disease outcome. The purpose of this paper is to compare recent advancements in our understanding of γδ T cells in humans, cattle, and mice and to discuss roles of γδ T cells in host response to mycobacterial infection.

γδ T Cells in Host Defense and Epithelial Cell Biology

Recent studies have demonstrated increased numbers of γδ T cells in a variety of human infectious as well as noninfectious diseases. In some cases γδ T cells could be shown to destroy infected or transformed cells. Advances in the identification of ligands recognized by γδ T cells and the development of animal model systems to study these cells in vivoshould overcome some of the major obstacles currently preventing a better understanding of γδ T cell function in immune responses. As we gain this knowledge it may become possible to design therapeutic strategies exploiting unique properties of γδ T cells to promote more effective immunity.