Skip to main content
NCBI home page
Cellular and Molecular Immunology logoLink to Cellular and Molecular Immunology
. 2010 Oct 11;7(6):409–413. doi: 10.1038/cmi.2010.50

Current progress in γδ T-cell biology

Jianlei Hao 1, Xiaoli Wu 1, Siyuan Xia 1, Zheng Li 1, Ti Wen 1, Na Zhao 1, Zhenzhou Wu 1, Puyue Wang 1, Liqing Zhao 1, Zhinan Yin 1
PMCID: PMC4002965  PMID: 21042298

Abstract

T lymphocytes bearing γ- and δ-chain T-cell receptor heterodimers are named γδ T cells. Interestingly, γδ and αβ T cells share the same progenitors, and they undergo a fate decision in the thymus. Functional differentiation of γδ T cells occurs both inside and outside the thymus. Antigen recognition of γδ T-cell receptors is very unique, and the responses frequently exhibit innate characteristics. Nevertheless, peripheral γδ T cells exert a number of effector and regulatory functions. γδ T cells rapidly produce cytokines like interferon (IFN)-γ and IL-17 and promote inflammation, partly due to the inherent epigenetic and transcriptional programs, which facilitates a quick and extensive response. Moreover, γδ T cells lyse target cells directly, and this is necessary for pathogen or tumor clearance. γδ T cells can even serve as regulatory cells, and may contribute to immune suppression. Orchestration of γδ T-cell and other immune cell interactions may be critical for host defense and immune regulation. Recently, γδ T cells have been used for immunotherapy for infectious diseases and malignancy. In this review, we summarize the abstracts presented at the recent γδ T cell Conference held from 19 to 21 May 2010, in Kiel, Germany (please see the website for details: http://www.gammadelta-conference.uni-kiel.de/index.html).

Keywords: γδ T cells, immunotherapy, innate immunity

Introduction

So far, two subsets of T cells have been defined: αβ T cells and γδ T cells. Peptide-major histocompatibility complex-specific T-cell responses are known to be achieved by αβ T cells, while γδ T-cell biology is much less studied. Mice without γδ T cells are highly susceptible to diseases and tumor, suggesting an important role of γδ T cells in defense. By current technology in cellular and molecular immunology, researchers revealed that γδ T cells produce a series of cytokines in pathology, and the effector γδ T cells play an indispensable role in pathogen elimination, immune regulation and autoimmunity. As a group of innate immune cells, γδ T cells respond rapidly and expand efficiently when stimulated by antigens or cytokines. γδ T cells may be a good target for modulation of immune responses in human diseases. In recent years, a lot of researchers focused on the γδ T-cell development, function and therapeutic use.

Development

Several factors that contribute to γδ T-cell fate decisions have been identified, e.g. SOX13,1 Id3,2 T-cell receptor (TCR) signal strength, etc.3, 4, 5, 6, 7, 8, 9, 10 However, mechanisms of functional differentiation of effector γδ T cells are poorly understood.11, 12, 13, 14 Key cytokines produced by γδ T cells are interferon (IFN)-γ,15, 16, 17, 18, 19 tumor-necrosis factor (TNF)-α20, 21 and IL-17,22, 23, 24, 25, 26 and are critical for pathogen clearance, immune regulation and autoimmunity. Shibata and colleagues reported that the basic helix–loop–helix protein HES1 is specifically expressed in IL-17+ γδ T cells and is required for the differentiation of naturally occurring IL-17+ γδ T cells in the thymus. In addition, Powolny-Budnicka and colleagues reported that RelA and RelB within different thymocyte subpopulations control IL-17 production by γδ T cells and contribute to the host's ability to fight bacterial infections in vivo. CD27+ γδ T cells produce IFN-γ while CD27− γδ T cells produce IL-17.27 However, the role and extent of γδ TCR signaling, and how these signals cooperate with other thymic inputs to control CD27+ and CD27− γδ T-cell development, remain unclear. Pang and colleagues reported that manipulating the strength of γδ TCR signals can regulate CD27+ and CD27− γδ T-cell development and produce IFN-γ and IL-17, respectively. Moreover, Michel and colleagues found that γδ T-cell progenitors with the highest potential to produce IL-17 compose a small subset of cells characterized by high levels of receptor for a key thymic cytokine. Provision of this cytokine dramatically skews thymocytes towards IL-17 differentiation. Conversely, γδ T cells with the highest potential to produce IFN-γ are promoted by engaging CD27.

Although the CD70–CD27 interaction was reported to be important for thymic differentiation of IFN-γ-producing γδ T cells,27 the role of this signal in the peripheral γδ T cells remains unknown. Ribot and colleagues reported that CD27 is also required for peripheral expansion of the effector CD27+ γδ T cells upon herpes and malaria infection in mice. Similarly, deBarros and colleagues in the same laboratory reported CD27 is expressed by ∼80% of adult Vγ9 peripheral blood lymphocytes and by similar proportion of Vγ9+ thymocytes derived from paediatric thymic biopsies. CD27 signals promote the secretion of IFN-γ and TNF-α by human Vγ9Vδ2 γδ T cells, but may not affect γδ T-cell proliferation.

Because γδ TCR itself is the only phenotypic marker for tracking thymocytes committed to the γδ T-cell lineage, investigation of γδ T-cell development has relied mainly on monitoring of the expression of γδ TCR. Therefore, it has been impossible to identify γδ T-cell precursors before they express γδ TCR. Prinz and colleagues developed TCRd-H2BEGFP mice expressing a stable reporter gene ‘knocked into' the Tcrd constant region gene.28 Using the reporter mice, Ravens and colleagues explored the ontogeny of IL-17A-producing γδ T cells in embryonic thymus. They found higher frequencies of IL-17A-producing γδ T cells in CCR7−/−, but lower ones in CCR9−/− TCRd-H2BEGFP reporter mice, suggesting that signals from the thymic cortex may facilitate the development of IL-17A-producing γδ T cells.

Antigens and costimulatory molecules

To date, researchers have not fully elucidated the ligands for γδ T cells, although several ligands of γδ TCR have been identified.29 Quite surprisingly, there are significant differences between mice and humans in the range of ligands recognized by the γδ TCR. While phosphorylated small molecules that are intermediates of the microbial mevalonate metabolic pathway (‘phosphoantigens') are prominent ligands for the human Vγ9Vδ2 T cells, such ligands are not recognized by murine γδ T cells. Not taking into account such species differences, γδ TCRs recognize T10/T22,30, 31, 32, 33 CD1c,34, 35 major histocompatibility complex class I-related chains A and B (MICA/B),36 phosphoantigens37 and ATP synthase-1/apolipoprotein A-1 complex.38 Striegl and colleagues reported that CD1d is able to bind and present tetra-acylated phospholipid cardiolipin to a subset of CL-responsive γδ T cells that exist in the spleen and liver of healthy mice. Born and colleagues found that insulin-derived peptide B:9-23 is a ligand for murine γδ TCRs. Although insulin peptide B:9-23 can also stimulate αβ T cells, the γδ T-cell response to insulin peptide B:9-23 does not require any accessory cells. Chain and colleagues are using recombinant soluble γδ TCRs to find new ligands. Their laboratory (headed by Born) is currently focusing on identifying ligands for Vγ1Vδ6.3 and Vγ6Vδ1 TCRs. Detecting ligands of γδ TCR multimers provides us with an opportunity to determine when, where and by whom γδ TCR ligands are expressed.

It was reported that human γδ TCRs recognize F1-ATPase and also the phosphoantigen isopentenyl pyrophosphate (IPP).37, 38 Mookerjee-Basu and colleagues reported that F1-ATPase serves as an Ag-presenting molecule in this process. Immobilized F1 complexes can induce an intracellular calcium signal in IPP-specific Vγ9Vδ2 γδ T cells in the presence of soluble IPP and in the absence of any cell–cell interactions.

NKG2D ligands are intriguing because of their multiplicity.39 MICA was reported to activate NKG2D expressed on most human γδ T cells,40 Vantourout and colleagues studied the activation of γδ T cells by MICA and the functional implications of its polymorphism. They observed broad diversity of the responses to different alleles of MICA.

Recently, Toll-like receptors were found to be expressed in γδ T cells.25 Here, Marischen and colleagues reported that human γδ T cells express the Nod-like receptor NOD2 and thereby can react to its ligand muramyl dipeptide by increased IFN-γ secretion.

Although negative regulation of αβ T cells has been widely studied, those of γδ T cells are less well characterized. Specifically, cytotoxic T-lymphocyte antigen-4 and the immunoinhibitory receptor-programmed death-1 (PD-1) are major co-inhibitors of αβ T cells and anti-cytotoxic T-lymphocyte antigen-4 and PD-1 monoclonal antibodies are used in clinical trials.41 Gertner-Dardenne and colleagues reported that PD-1 is readily expressed on resting Vγ9Vδ2 γδ T cells and its expression was regulated during phosphoantigenic activation. Furthermore, a blockade of PD-1 resulted in increased phosphoantigen-induced γδ T-cell proliferation and Th1 cytokine secretion. Altogether, these data suggest that PD-1 is a major inhibitory functional receptor on Vγ9Vδ2 T cells and is also a potential therapeutic target for designing measures to modulate the γδ T-cell response. Consistently, Beck and colleagues reported that the PD-1 pathway is a potentially important mechanism by which γδ T cells are either functionally impaired or otherwise exhausted in tumor-bearing mice.

Immune regulation

γδ T cells are highly cytolytic lymphocytes that produce large amounts of proinflammatory cytokines during immune responses to multiple pathogens.42, 43 However, how γδ T-cell functions might be regulated remains unclear. Gonçalves-Sousa and colleagues reported that murine CD4+CD25+Foxp3+ regulatory T cells abolished key effector functions and proliferation of γδ T cells both in vitro and in vivo. They further showed that suppression was dependent on cellular contact between regulatory and γδ T cells, and was partially mediated by glucocorticoid-induced TNF receptor-related protein. These data revealed a novel mechanism by which γδ T-cell function is regulated, and suggested that endogenous regulatory T cells may prevent the desired effects of γδ T cell-based immunotherapies.

γδ T cells play suppressive roles under some conditions.44, 45 Otsuka and colleagues classified a fraction of γδ T cells in the lymph nodes and all epidermal γδ T cells in the skin, but not on dermal γδ T cells in the steady state. These cells (IL-10+) extensively inhibited dendritic cell (DC)-dependent T-cell proliferation. Furthermore, they identified a specific marker of these regulatory γδ T cells.

Gut intraepithelial lymphocytes constitute one of the largest T-cell compartments, and include large numbers of γδ T cells.46 Abeler-Dörner and colleagues described a novel means to establish viable, resting γδ intraepithelial lymphocytes in culture for at least 3 weeks. They found activated intraepithelial lymphocytes induced the juxtaposed epithelial cells to substantially upregulate IL-6. The secretion of IL-6 is regulated by the epithelial surface molecule butyrophilin-like 1, which is specifically expressed by cells in the intestine. This network may jointly regulate antimicrobial responses, inflammation-associated carcinogenesis and food allergies.

Function in infectious diseases

γδ T cells are important in virus and bacteria clearance.47, 48, 49, 50 γδ T cells may undergo a dysfunction during infection: Christopoulos and colleagues reported that, in patients with thymoma, expanded γδ T cells bear a dysfunctional γδ TCR that possesses the characteristics of altered stability and glycosylation, resulting in lowered reactivity to antigens. Furthermore, Meraviglia and colleagues claimed that Mycobacterium tuberculosis-infected DCs can only partially and ineffectively activate Vγ9Vδ2 T cells into a central memory type but not effector type.

While γδ T cells are dysfunctional in infectious diseases, many substances can induce activation and expansion of them. Cimini and colleagues reported that IPH-1101 (i.e., bromohydrin pyrophosphate)-activated Vγ9Vδ2 T cells are able to mediate a direct antiviral activity and to improve adaptive long-lasting immune response in hepatitis C virus (HCV) patients after IFN-α treatment. Lin and colleagues found that as Vγ9Vδ2 T cells can be activated by (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), higher HMBPP-producing capacity of the causative pathogen predicts a better outcome in first-time episodes of bacterial peritonitis.

DCs, vaccine, microbial load, etc. are also involved in γδ T-cell activation.23, 25, 51, 52, 53, 54 Moens and colleagues showed that human neonatal DC-derived IL-23 combined with specific TCR signaling drives the generation of neonatal Vγ9Vδ2 T cells equipped with a range of cytotoxic mediators and distinct subpopulations producing IFN-γ and IL-17. Dimova and colleagues revealed that the immune response after bacillus Calmette–Guérin vaccination of infants can drive γδ T cells into an effector cell type that produce IFN-γ and mediate cytotoxicity. Costa and colleagues found that the extracellular malaria merozoite is a new activator and target of the antiparasitic activity of γδ T cells. With granulysin rather than perforin, Vγ9Vδ2 T cells can inhibit multiplication of Plasmodium falciparum blood stages in vitro. By establishing an animal model, Wang and colleagues explored that recall expansion of Vγ2Vδ2 T cells in Mycobacterium- or Listeria-infected monkeys depends on Th17-associated cytokines from host together with primed and boosted microbial loads.

Ag recognition is important in γδ T cell-mediated virus and bacteria clearance. Li and colleagues demonstrated that γδ T cells are effector cells in parasite elimination in AIM (apoptosis inhibitor expressed by macrophages)−/− mice. Legrand and colleagues observed that human eosinophil granulocytes express a functional γδ TCR complex and may contribute to defense to Mycobacteria infection and tumors.

Rajoriya and colleagues reported that the frequency of CD161+ γδ cells in peripheral blood is reduced in HCV-infected patients. Furthermore, CD161+ γδ cells from HCV+ patients expressed higher levels of CXCR6, CD38 and CD69 compared to those of healthy populations. It revealed that CD161+ γδ cells are more active and with higher ‘liver homing' potential concentrated in the liver in HCV patients. Wu and colleagues detected that the frequency of Vδ2 γδ T cells is significantly decreased in immune-active chronic hepatitis B patients both in the blood and in the liver. Moreover, γδ T cells are more active and secrete more TNF-α in immune-active chronic hepatitis B patients when compared with healthy control patients. Vδ2 γδ T cells are closely linked with liver damage and may play a protective role. Pauza and colleagues observed that lymphocytes were severely impacted in HIV controllers (i.e., patients whose HIV infection does not progress to AIDS disease), although a unique Vγ2Vδ2 T-cell population that sustains the phosphoantigen response can guard against damage by immunodeficiency viruses.

Function in antitumor reaction

γδ T cells are potent effectors of innate immunity and are involved in antitumor immune responses.18, 19, 55, 56, 57 A lot of studies are currently focusing on the antitumor effector subset of human γδ T cells. Knight and colleagues examined the potential of γδ T cells to lyse tumor targets in vitro and reported that Vδ1 γδ T cells showed specific cytotoxicity to many tumor cell lines, the most prominent of which were glioblastoma, myeloma, colon and lymphoma. Similarly, Devaud and colleagues reported that Vδ1 γδ T cells significantly suppress colon cancer cells. There are also reports focusing on the Vδ2 γδ T cell-mediated tumor immunity. Gertner-Dardenne and colleagues reported mice receiving Vγ9Vδ2 T cells exhibited superior survival rates compared to untreated controls upon transfer of acute monocytic leukemia cells. The CD226 ligands poliovirus receptor and Nectin-2 play an important role as tumor cell-expressed targets for the Vγ9Vδ2 T cell-mediated killing of acute monocytic leukemia blasts.

Molecular mechanisms underlying lymphoma recognition by γδ T cells remain unclear. Lança and colleagues reported that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to γδ T cell-mediated cytolysis. Consistently, a blockade of NKG2D, the receptor for ULBP1 expressed on all Vγ9 γδ T cells, significantly inhibits lymphoma cell killing. Specific loss-of-function studies demonstrate that the role of ULBP1 is non-redundant, highlighting a thus far unique physiological relevance for tumor recognition by γδ T cells. Importantly, they observed a very wide spectrum of ULBP1 expression level in primary biopsies obtained from lymphoma and leukemia patients. This study also proposes that ULBP1 may be used as a leukemia/lymphoma biomarker in upcoming clinical trials.

Function in tissue repair and inflammation

Skin γδ T cells were found to be critical in wound healing,58, 59, 60, 61, 62 and IL-17 was reported to be elevated in patients with inflammatory skin diseases.63 However, the role of IL-17 in cutaneous wound healing, and whether it is produced by skin γδ T cells, are less clear. Here, Büchau and colleagues reported that cultured skin γδ T cells rapidly produce IL-17A upon TCR activation. Furthermore, IL-23 and IL-1β exposure led to IL-17A secretion. Using an in vivo wounding model, they found substantial and transient IL-17 production by skin γδ T cells, with an IL-17 deficiency leading to a defect in wound repair. These results implied a critical role of γδ T cell-produced IL-17 in cutaneous immunity and wound healing.

One example of γδ T-cell dysfunction is the skin complications associated with obesity and metabolic disease. Taylor and colleagues reported that elevated glucose impairs the ability of skin γδ T cells to proliferate, and leads to a loss of γδ T-cell responsiveness to stimulation.64 This suggests that the environment in metabolic disease has negative effects on the homeostasis and functionality of skin lymphocytes and renders them unresponsive to epithelial damage, and may provide new and previously unrecognized therapeutic targets for treating complications associated with metabolic disease.

Immunotherapy

Some preclinical investigations indicated that γδ T cells may play a certain role in antitumor effects and many phosphoantigens can promote the function of γδ T cells in vitro.57, 65 Capietto and colleagues reported that bromohydrin pyrophosphate-treated Vγ9Vδ2 T cells can bypass TGF-β-mediated immunosuppression in current cancer immunotherapy. Castella and colleagues observed that dysfunction of Vγ9Vδ2 T cells in multiple myeloma patients can be fully recovered by zoledronic acid and tumor-associated antigen-treated DCs. Furthermore, Cimini and colleagues identified that zoledronic acid can enhance the antitumor response to glioma cell lines of Vδ2 T lymphocytes.

Animal models have been established to identify the functions of γδ T cells in tumor therapy. Siegers and colleagues developed a preclinical xenograft model of chronic myeloid leukemia to investigate the cytotoxicity of γδ T cells. With this model, they also found that the cytotoxicities of Vδ1 and Vδ2 T cells are different when compared against Philadelphia chromosome-positive and B-chronic lymphocytic leukemia-derived leukemic cells. Laws and colleagues used a marmoset model to assess the antitumor function of IPH1201 (a phosphoantigen, can specifically activate γδ T cells) in vivo. Subcutaneous dosing with IPH1201 plus IL-2 caused specific expansion of Vγ9 T cells, suggesting marmoset may be an appropriate model for testing IPH1201 as an immunotherapy.

As accumulating evidence shows that γδ T cells, especially Vγ9Vδ2 T cells, have antitumor effects both in vitro and in animal models, researchers have tested their function in clinical therapies in patients.66, 67, 68 The frequency of γδ T cells is correlated to the patients' clinical survival rate. Tanaka and colleagues reported that in advanced renal cell carcinoma, a higher survival rate after surgery is correlated to higher γδ T-cell frequency in patients' peripheral blood.

Phosphoantigen and fungal immunomodulators play an important role in γδ T cell-mediated immunotherapy. Dunne and colleagues revealed that HMBPP-activated Vγ9Vδ2 T cells strongly promotes Th1 responses. Kunzmann and colleagues observed that zoledronic acid plus IL-2-treated γδ T cells can induce significant immunological responses, but the objective clinical response rate is low and restricted to hematological malignancies. In order to improve antitumor function, Binda and colleagues optimized the immunotherapeutic potential of zoledronate-activated Vγ9Vδ2 T cells in many ways. Li and colleagues observed that rapamycin modulated IPP/IL-2-induced Vγ2Vδ2 T-cell proliferation in a dose-dependent manner.

γδ TCRs are quite important in the recognition of tumor cells. Marcu-Malina and colleagues retrovirally transduced tumor-specific high-affinity γδ TCRs into human αβ T cells. After stimulation by phosphoantigens, this kind of modified αβ T cells can be effective against a broad panel of cancer cells while ignoring normal cells. Pérez and colleagues established a prognostic value system to test γδ T-cell responses in breast cancer patients during zoledronate therapy.

In addition to tumor immunotherapy, γδ T cells are also considered in other diseases. Hawchar and colleagues reported that TEMRA (terminally differentiated effector memory, CD45RA+CD27−) Vδ2− γδ T lymphocytes are endowed with anticytomegalovirus potential in kidney transplant recipients and can be expanded by IL-2 and IL-15. Dorp and colleagues detected that γδ T cells present in patients after allogeneic transplantation have the potential to eradicate cytomegalovirus-infected fibroblasts and to spread an immune response to αβ T cells via DC maturation. Bol-Schoenmakers and colleagues found that murine intestinal γδ T cells play a regulatory role during establishment of allergic sensitization to peanuts, suggesting that targeting intestinal γδ T cells may provide preventing and therapeutic strategies for food allergy.

Summary remarks

Where are we heading to from here with respect to the biological function of γδ T cells? After several open discussion sessions, it became evident that one important area is to bring together the results from animal studies with those gained from human studies. Otherwise, two different languages (‘mice' and ‘human') would hurdle the understanding of biological function of γδ T cells. Defining the ligands of γδ T cells is still far from the reach. Cytokine production by γδ T cells may regulate the function of αβ T cells and other antigen-presenting cells, and this area may open the window for understanding the whole picture of immune responses. The role of γδ T cells in emerging and chronic infections needs more attention and potential therapy may derive from manipulating the function of these γδ T cells. Finally, the potential therapeutic role of γδ T cells in malignancy has clearly shed new light in tumor immunotherapy. No doubt, exciting results will be further discussed at the next 2012 γδ T cell Conference to be held in Rome, Italy. All roads lead to Rome, and the same is true for the mysterious γδ T cells.

Acknowledgments

We are grateful to Dr Mark Bartlam and Dr Dieter Kabelitz for editing the manuscript. We are grateful to the organizers, Dr Dieter Kabelitz and Dr Daniela Wesch; they made this conference unforgettable. Due to the length of this report, we sincerely apologize to those participants for not mentioning their exciting results here. This work was supported by grants from the National Basic Research Program of China (2007CB914801) and the National Outstanding Young Scientist Award of National Natural Science Foundation of China (30725015).

References

  1. Melichar HJ, Narayan K, Der SD, Hiraoka Y, Gardiol N, Jeannet G, et al. Regulation of gammadelta versus alphabeta T lymphocyte differentiation by the transcription factor SOX13. Science. 2007;315:230–233. doi: 10.1126/science.1135344. [DOI] [PubMed] [Google Scholar]
  2. Lauritsen JP, Wong GW, Lee SY, Lefebvre JM, Ciofani M, Rhodes M, et al. Marked induction of the helix–loop–helix protein Id3 promotes the gammadelta T cell fate and renders their functional maturation Notch independent. Immunity. 2009;31:565–575. doi: 10.1016/j.immuni.2009.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Haks MC, Lefebvre JM, Lauritsen JP, Carleton M, Rhodes M, Miyazaki T, et al. Attenuation of gammadelta TCR signaling efficiently diverts thymocytes to the alphabeta lineage. Immunity. 2005;22:595–606. doi: 10.1016/j.immuni.2005.04.003. [DOI] [PubMed] [Google Scholar]
  4. Hayes SM, Li L, Love PE. TCR signal strength influences alphabeta/gammadelta lineage fate. Immunity. 2005;22:583–593. doi: 10.1016/j.immuni.2005.03.014. [DOI] [PubMed] [Google Scholar]
  5. Kreslavsky T, Garbe AI, Krueger A, von Boehmer H. T cell receptor-instructed alphabeta versus gammadelta lineage commitment revealed by single-cell analysis. J Exp Med. 2008;205:1173–1186. doi: 10.1084/jem.20072425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ciofani M, Knowles GC, Wiest DL, von Boehmer H, Zuniga-Pflucker JC. Stage-specific and differential notch dependency at the alphabeta and gammadelta T lineage bifurcation. Immunity. 2006;25:105–116. doi: 10.1016/j.immuni.2006.05.010. [DOI] [PubMed] [Google Scholar]
  7. Garbe AI, Krueger A, Gounari F, Zuniga-Pflucker JC, von Boehmer H. Differential synergy of Notch and T cell receptor signaling determines alphabeta versus gammadelta lineage fate. J Exp Med. 2006;203:1579–1590. doi: 10.1084/jem.20060474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Tanigaki K, Tsuji M, Yamamoto N, Han H, Tsukada J, Inoue H, et al. Regulation of alphabeta/gammadelta T cell lineage commitment and peripheral T cell responses by Notch/RBP-J signaling. Immunity. 2004;20:611–622. doi: 10.1016/s1074-7613(04)00109-8. [DOI] [PubMed] [Google Scholar]
  9. Washburn T, Schweighoffer E, Gridley T, Chang D, Fowlkes BJ, Cado D, et al. Notch activity influences the alphabeta versus gammadelta T cell lineage decision. Cell. 1997;88:833–843. doi: 10.1016/s0092-8674(00)81929-7. [DOI] [PubMed] [Google Scholar]
  10. Boyden LM, Lewis JM, Barbee SD, Bas A, Girardi M, Hayday AC, et al. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells. Nat Genet. 2008;40:656–662. doi: 10.1038/ng.108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Silva-Santos B, Pennington DJ, Hayday AC. Lymphotoxin-mediated regulation of gammadelta cell differentiation by alphabeta T cell progenitors. Science. 2005;307:925–928. doi: 10.1126/science.1103978. [DOI] [PubMed] [Google Scholar]
  12. Jensen KD, Su X, Shin S, Li L, Youssef S, Yamasaki S, et al. Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity. 2008;29:90–100. doi: 10.1016/j.immuni.2008.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pennington DJ, Silva-Santos B, Shires J, Theodoridis E, Pollitt C, Wise EL, et al. The inter-relatedness and interdependence of mouse T cell receptor gammadelta+ and alphabeta+ cells. Nat Immunol. 2003;4:991–998. doi: 10.1038/ni979. [DOI] [PubMed] [Google Scholar]
  14. Kreslavsky T, Savage AK, Hobbs R, Gounari F, Bronson R, Pereira P, et al. TCR-inducible PLZF transcription factor required for innate phenotype of a subset of gammadelta T cells with restricted TCR diversity. Proc Natl Acad Sci USA. 2009;106:12453–12458. doi: 10.1073/pnas.0903895106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Yin Z, Zhang DH, Welte T, Bahtiyar G, Jung S, Liu L, et al. Dominance of IL-12 over IL-4 in gamma delta T cell differentiation leads to default production of IFN-gamma: failure to down-regulate IL-12 receptor beta 2-chain expression. J Immunol. 2000;164:3056–3064. doi: 10.4049/jimmunol.164.6.3056. [DOI] [PubMed] [Google Scholar]
  16. Yin Z, Chen C, Szabo SJ, Glimcher LH, Ray A, Craft J. T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-gamma by gammadelta T cells. J Immunol. 2002;168:1566–1571. doi: 10.4049/jimmunol.168.4.1566. [DOI] [PubMed] [Google Scholar]
  17. Chen L, He W, Kim ST, Tao J, Gao Y, Chi H, et al. Epigenetic and transcriptional programs lead to default IFN-gamma production by gammadelta T cells. J Immunol. 2007;178:2730–2736. doi: 10.4049/jimmunol.178.5.2730. [DOI] [PubMed] [Google Scholar]
  18. Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med. 2003;198:433–442. doi: 10.1084/jem.20030584. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. He W, Hao J, Dong S, Gao Y, Tao J, Chi H, et al. Naturally activated Vgamma4 gammadelta T cells play a protective role in tumor immunity through expression of eomesodermin. J Immunol. 2010;185:126–133. doi: 10.4049/jimmunol.0903767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Subauste CS, Chung JY, Do D, Koniaris AH, Hunter CA, Montoya JG, et al. Preferential activation and expansion of human peripheral blood gamma delta T cells in response to Toxoplasma gondii in vitro and their cytokine production and cytotoxic activity against T. gondii-infected cells. J Clin Invest. 1995;96:610–619. doi: 10.1172/JCI118076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Wang L, Das H, Kamath A, Bukowski JF. Human V gamma 2V delta 2 T cells produce IFN-gamma and TNF-alpha with an on/off/on cycling pattern in response to live bacterial products. J Immunol. 2001;167:6195–6201. doi: 10.4049/jimmunol.167.11.6195. [DOI] [PubMed] [Google Scholar]
  22. Roark CL, French JD, Taylor MA, Bendele AM, Born WK, O'Brien RL. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. J Immunol. 2007;179:5576–5583. doi: 10.4049/jimmunol.179.8.5576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Hamada S, Umemura M, Shiono T, Tanaka K, Yahagi A, Begum MD, et al. IL-17A produced by gammadelta T cells plays a critical role in innate immunity against listeria monocytogenes infection in the liver. J Immunol. 2008;181:3456–3463. doi: 10.4049/jimmunol.181.5.3456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Roark CL, Simonian PL, Fontenot AP, Born WK, O'Brien RL. Gammadelta T cells: an important source of IL-17. Curr Opin Immunol. 2008;20:353–357. doi: 10.1016/j.coi.2008.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31:321–330. doi: 10.1016/j.immuni.2009.06.020. [DOI] [PubMed] [Google Scholar]
  26. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31:331–341. doi: 10.1016/j.immuni.2009.08.001. [DOI] [PubMed] [Google Scholar]
  27. Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Roberts SJ, et al. CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets. Nat Immunol. 2009;10:427–436. doi: 10.1038/ni.1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Prinz I, Sansoni A, Kissenpfennig A, Ardouin L, Malissen M, Malissen B. Visualization of the earliest steps of gammadelta T cell development in the adult thymus. Nat Immunol. 2006;7:995–1003. doi: 10.1038/ni1371. [DOI] [PubMed] [Google Scholar]
  29. O'Brien RL, Roark CL, Jin N, Aydintug MK, French JD, Chain JL, et al. gammadelta T-cell receptors: functional correlations. Immunol Rev. 2007;215:77–88. doi: 10.1111/j.1600-065X.2006.00477.x. [DOI] [PubMed] [Google Scholar]
  30. Crowley MP, Reich Z, Mavaddat N, Altman JD, Chien Y. The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the gammadelta T cell, G8. J Exp Med. 1997;185:1223–1230. doi: 10.1084/jem.185.7.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Matis LA, Cron R, Bluestone JA. Major histocompatibility complex-linked specificity of gamma delta receptor-bearing T lymphocytes. Nature. 1987;330:262–264. doi: 10.1038/330262a0. [DOI] [PubMed] [Google Scholar]
  32. Shin S, El-Diwany R, Schaffert S, Adams EJ, Garcia KC, Pereira P, et al. Antigen recognition determinants of gammadelta T cell receptors. Science. 2005;308:252–255. doi: 10.1126/science.1106480. [DOI] [PubMed] [Google Scholar]
  33. Adams EJ, Strop P, Shin S, Chien YH, Garcia KC. An autonomous CDR3delta is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by gammadelta T cells. Nat Immunol. 2008;9:777–784. doi: 10.1038/ni.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Porcelli S, Brenner MB, Greenstein JL, Balk SP, Terhorst C, Bleicher PA. Recognition of cluster of differentiation 1 antigens by human CD4−CD8-cytolytic T lymphocytes. Nature. 1989;341:447–450. doi: 10.1038/341447a0. [DOI] [PubMed] [Google Scholar]
  35. Spada FM, Grant EP, Peters PJ, Sugita M, Melian A, Leslie DS, et al. Self-recognition of CD1 by gamma/delta T cells: implications for innate immunity. J Exp Med. 2000;191:937–948. doi: 10.1084/jem.191.6.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Groh V, Steinle A, Bauer S, Spies T. Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science. 1998;279:1737–1740. doi: 10.1126/science.279.5357.1737. [DOI] [PubMed] [Google Scholar]
  37. Tanaka Y, Morita CT, Nieves E, Brenner MB, Bloom BR. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature. 1995;375:155–158. doi: 10.1038/375155a0. [DOI] [PubMed] [Google Scholar]
  38. Scotet E, Martinez LO, Grant E, Barbaras R, Jeno P, Guiraud M, et al. Tumor recognition following Vgamma9Vdelta2 T cell receptor interactions with a surface F1-ATPase-related structure and apolipoprotein A–I. Immunity. 2005;22:71–80. doi: 10.1016/j.immuni.2004.11.012. [DOI] [PubMed] [Google Scholar]
  39. Diefenbach A, Jamieson AM, Liu SD, Shastri N, Raulet DH. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 2000;1:119–126. doi: 10.1038/77793. [DOI] [PubMed] [Google Scholar]
  40. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science. 1999;285:727–729. doi: 10.1126/science.285.5428.727. [DOI] [PubMed] [Google Scholar]
  41. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–548. doi: 10.1146/annurev.immunol.23.021704.115611. [DOI] [PubMed] [Google Scholar]
  42. Born WK, Yin Z, Hahn YS, Sun D, O'Brien RL. Analysis of gammadelta T cell functions in the mouse. J Immunol. 2010;184:4055–4061. doi: 10.4049/jimmunol.0903679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Bonneville M, O'Brien RL, Born WK. Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol. 2010;10:467–478. doi: 10.1038/nri2781. [DOI] [PubMed] [Google Scholar]
  44. Peng G, Wang HY, Peng W, Kiniwa Y, Seo KH, Wang RF. Tumor-infiltrating gammadelta T cells suppress T and dendritic cell function via mechanisms controlled by a unique Toll-like receptor signaling pathway. Immunity. 2007;27:334–348. doi: 10.1016/j.immuni.2007.05.020. [DOI] [PubMed] [Google Scholar]
  45. Vincent MS, Roessner K, Lynch D, Wilson D, Cooper SM, Tschopp J, et al. Apoptosis of Fashigh CD4+ synovial T cells by Borrelia-reactive Fas-ligandhigh gammadelta T cells in Lyme arthritis. J Exp Med. 1996;184:2109–2118. doi: 10.1084/jem.184.6.2109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Hayday AC. gammadelta cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol. 2000;18:975–1026. doi: 10.1146/annurev.immunol.18.1.975. [DOI] [PubMed] [Google Scholar]
  47. Vermijlen D, Brouwer M, Donner C, Liesnard C, Tackoen M, van Rysselberge M, et al. Human cytomegalovirus elicits fetal gammadelta T cell responses in utero. J Exp Med. 2010;207:807–821. doi: 10.1084/jem.20090348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Mombaerts P, Arnoldi J, Russ F, Tonegawa S, Kaufmann SH. Different roles of alpha beta and gamma delta T cells in immunity against an intracellular bacterial pathogen. Nature. 1993;365:53–56. doi: 10.1038/365053a0. [DOI] [PubMed] [Google Scholar]
  49. Shen Y, Zhou D, Qiu L, Lai X, Simon M, Shen L, et al. Adaptive immune response of Vgamma2Vdelta2+ T cells during mycobacterial infections. Science. 2002;295:2255–2258. doi: 10.1126/science.1068819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Hiromatsu K, Yoshikai Y, Matsuzaki G, Ohga S, Muramori K, Matsumoto K, et al. A protective role of gamma/delta T cells in primary infection with Listeria monocytogenes in mice. J Exp Med. 1992;175:49–56. doi: 10.1084/jem.175.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Dieli F, Caccamo N, Meraviglia S, Ivanyi J, Sireci G, Bonanno CT, et al. Reciprocal stimulation of gammadelta T cells and dendritic cells during the anti-mycobacterial immune response. Eur J Immunol. 2004;34:3227–3235. doi: 10.1002/eji.200425368. [DOI] [PubMed] [Google Scholar]
  52. O'Brien RL, Happ MP, Dallas A, Palmer E, Kubo R, Born WK. Stimulation of a major subset of lymphocytes expressing T cell receptor gamma delta by an antigen derived from Mycobacterium tuberculosis. . Cell. 1989;57:667–674. doi: 10.1016/0092-8674(89)90135-9. [DOI] [PubMed] [Google Scholar]
  53. French JD, Roark CL, Born WK, O'Brien RL. gammadelta T cell homeostasis is established in competition with alphabeta T cells and NK cells. Proc Natl Acad Sci USA. 2005;102:14741–14746. doi: 10.1073/pnas.0507520102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Constant P, Davodeau F, Peyrat MA, Poquet Y, Puzo G, Bonneville M, et al. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science. 1994;264:267–270. doi: 10.1126/science.8146660. [DOI] [PubMed] [Google Scholar]
  55. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, et al. Regulation of cutaneous malignancy by gammadelta T cells. Science. 2001;294:605–609. doi: 10.1126/science.1063916. [DOI] [PubMed] [Google Scholar]
  56. Girardi M, Glusac E, Filler RB, Roberts SJ, Propperova I, Lewis J, et al. The distinct contributions of murine T cell receptor (TCR)gammadelta+ and TCRalphabeta+ T cells to different stages of chemically induced skin cancer. J Exp Med. 2003;198:747–755. doi: 10.1084/jem.20021282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Kabelitz D, Wesch D, He W. Perspectives of gammadelta T cells in tumor immunology. Cancer Res. 2007;67:5–8. doi: 10.1158/0008-5472.CAN-06-3069. [DOI] [PubMed] [Google Scholar]
  58. Jameson J, Ugarte K, Chen N, Yachi P, Fuchs E, Boismenu R, et al. A role for skin gammadelta T cells in wound repair. Science. 2002;296:747–749. doi: 10.1126/science.1069639. [DOI] [PubMed] [Google Scholar]
  59. Jameson JM, Cauvi G, Witherden DA, Havran WL. A keratinocyte-responsive gamma delta TCR is necessary for dendritic epidermal T cell activation by damaged keratinocytes and maintenance in the epidermis. J Immunol. 2004;172:3573–3579. doi: 10.4049/jimmunol.172.6.3573. [DOI] [PubMed] [Google Scholar]
  60. Sharp LL, Jameson JM, Cauvi G, Havran WL. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat Immunol. 2005;6:73–79. doi: 10.1038/ni1152. [DOI] [PubMed] [Google Scholar]
  61. Girardi M, Lewis JM, Filler RB, Hayday AC, Tigelaar RE. Environmentally responsive and reversible regulation of epidermal barrier function by gammadelta T cells. J Invest Dermatol. 2006;126:808–814. doi: 10.1038/sj.jid.5700120. [DOI] [PubMed] [Google Scholar]
  62. Toulon A, Breton L, Taylor KR, Tenenhaus M, Bhavsar D, Lanigan C, et al. A role for human skin-resident T cells in wound healing. J Exp Med. 2009;206:743–750. doi: 10.1084/jem.20081787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suarez-Farinas M, Fuentes-Duculan J, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204:3183–3194. doi: 10.1084/jem.20071094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Taylor KR, Mills RE, Costanzo AE, Jameson JM. Gammadelta T cells are reduced and rendered unresponsive by hyperglycemia and chronic TNFalpha in mouse models of obesity and metabolic disease. PLoS One. 2010;5:e11422. doi: 10.1371/journal.pone.0011422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Chiplunkar S, Dhar S, Wesch D, Kabelitz D. gammadelta T cells in cancer immunotherapy: current status and future prospects. Immunotherapy. 2009;1:663–678. doi: 10.2217/imt.09.27. [DOI] [PubMed] [Google Scholar]
  66. Bouet-Toussaint F, Cabillic F, Toutirais O, Le Gallo M, Thomas de la Pintiere C, Daniel P, et al. Vgamma9Vdelta2 T cell-mediated recognition of human solid tumors. Potential for immunotherapy of hepatocellular and colorectal carcinomas. Cancer Immunol Immunother. 2008;57:531–539. doi: 10.1007/s00262-007-0391-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Bonneville M, Scotet E. Human Vgamma9Vdelta2 T cells: promising new leads for immunotherapy of infections and tumors. Curr Opin Immunol. 2006;18:539–546. doi: 10.1016/j.coi.2006.07.002. [DOI] [PubMed] [Google Scholar]
  68. Nedellec S, Bonneville M, Scotet E. Human Vgamma9Vdelta2 T cells: from signals to functions. Semin Immunol. 2010;22:199–206. doi: 10.1016/j.smim.2010.04.004. [DOI] [PubMed] [Google Scholar]

Articles from Cellular and Molecular Immunology are provided here courtesy of Nature Publishing Group

RESOURCES