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Células T gama delta e pele

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Getting Down to the Basics of γδ T Cells

In the new studies, the Havran and Wilson labs combined their expertise to answer the question: Which molecules are important for the activation of γδ T cells?

Wilson came to the current study after more than 20 years of work on the structure and function of αβ T cells. In 1996, his research team was the first to solve the structure of the αβ T cell receptor.

"To become activated in your body, T cells need recognition of an antigen by the T cell receptor," Wilson explained. "And from studies on αβ T cells, we know that for most T cells, one signal is not sufficient; they need a second, or costimulatory signal. For αβ T cells, that process has been well described. What we didn't know going into this current study whether γδ T cells required a second signal or not."

These two papers do in fact identify a junctional adhesion molecule, JAML, as a new costimulatory receptor for γδ T cells that binds to the ligand CAR (coxsackie and adenovirus receptor) expressed on keratinocytes.

"When there's damage or disease, the molecules we've identified are up-regulated," said Wilson, "and signals that are transmitted through their interaction with each other costimulate a T cell response that aids in tissue repair or killing of tumors."

Deborah Witherden, a senior staff scientist in Havran lab, was first author of the study titled "The adhesion molecule JAML is a costimulatory receptor for epithelial γδ T cell activation" (also with Petra Verdino, Stephanie Rieder, Olivia Garijo, Robyn Mills, Luc Teyton, Wilson, and Havran, all of Scripps Research, and Wolfgang Fischer of the Salk Institute). Verdino, a research associate in the Wilson lab, was first author of the companion publication, "The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K" (with Witherden, Havran, and Wilson).

A Combined Effort

The Witherden et al. study showed that γδ T cells in the skin and intestine require costimulatory signals delivered to the T cells by JAML binding to CAR on damaged keratinocytes. This leads to full activation of the γδ T cells and allows them to help heal wounds.

To understand the details of how γδ T cells are costimulated, scientists needed to get a three-dimensional view of the molecular interactions that go on between CAR, the ligand on the cell surface of damaged epithelial cells and its receptor JAML on γδ T cells. To do this, the scientists turned to a technique called x-ray crystallography, which involves making crystals of ordered arrays of protein and then blasting the frozen crystals with x-ray radiation. The atoms in the protein crystals cause the x-rays to diffract, and the scientists collect and analyze the pattern of diffraction to solve the atomic-level structure of the proteins.

Through this process, the Verdino et al. study determined the exact molecular details of how CAR on keratinocytes and JAML on γδ T cells interact. Furthermore, both studies revealed how the CAR-JAML interaction induces signaling events inside the γδ T cells that ultimately lead to proliferation and effector functions needed for wound repair.

But how did this basic-science finding translate into an animal model? The Witherden et al. study found that blocking the JAML interaction with CAR in mice led to defects in γδ T cell activation and subsequent wound healing. This confirmed that costimulatory signals from JAML are essential for γδ T cell responses to wounds.

"The best part of our combined effort," said Verdino, "is that we have put together a comprehensive picture of the role of JAML and CAR for γδ T cell function from various perspectives."

The Havran lab's next study, currently under way, will investigate a role for JAML and CAR interactions in activation of γδ T cells in humans. Chronic wounds are an increasing clinical problem for patients with diabetes, major burns, and pressure sores. The current studies suggest that JAML and CAR are potential targets for future treatments to stimulate faster wound healing in these patients.

"Identification of an epithelial γδ T cell specific activation molecule gives us a unique opportunity to manipulate the T cell response solely in these tissues," Witherden said.

These projects were supported by funding from the National Institute of Allergy and Infectious Diseases and National Cancer Institute of the National Institutes of Health, the Skaggs Institute for Chemical Biology at Scripps Research, the Leukemia and Lymphoma Society, and an Erwin-Schroedinger Fellowship of the Austrian Science Fund. Facilities and equipment used in the studies were made possible by grants from the National Science Foundation and Vincent J. Coates Foundation, as well as by Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source.
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The Junctional Adhesion Molecule JAML Is a Costimulatory Receptor for Epithelial {gamma}{delta} T Cell Activation

Deborah A. Witherden,1 Petra Verdino,2 Stephanie E. Rieder,1,* Olivia Garijo,1 Robyn E. Mills,1,{dagger} Luc Teyton,1 Wolfgang H. Fischer,4 Ian A. Wilson,2,3 Wendy L. Havran1,{ddagger}

Artigo da Investigative Dermatology

Journal of Investigative Dermatology (2006) 126, 25–31. doi:10.1038/sj.jid.5700003

Immunosurveillance and Immunoregulation by big gammadelta T Cells

Michael Girardi1

1Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA

Correspondence: Dr Michael Girardi, Associate Professor and Residency Director, Department of Dermatology, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520-8059, USA. Email:

Received 20 June 2005; Revised 19 August 2005; Accepted 2 September 2005.



Whereas the vast majority of T cells express a T-cell receptor (TCR) composed of alphabeta heterodimers, a smaller population expresses a gammadelta TCR. In contrast to alphabeta T cells, gammadelta T cells show less TCR diversity, are particularly enriched at epithelial surfaces and appear to respond to self-molecules that signal potential danger or cellular stress. In addition, various subsets of gammadelta T cells have shown antitumor and immunoregulatory activities. This review considers what has been discovered about the important cutaneous functions of gammadelta T cells through the study of mutant mice and offers perspectives on the roles of gammadelta T cells in human disease.


CDR3, complementarity-determining region 3; D, diversity (region); DETC, dendritic epidermal T cell; IEL, intraepithelial lymphocyte; J, junctional (region); MHC, major histocompatibility complex; MICA, major histocompatibility complex class I chain-related A; MICB, major histocompatibility complex class I chain-related B; NK, natural killer; NKT, natural killer T (cell); Rae-1, retinoic acid early-1; V, variable (region).

The coordinated responses of several different lymphoid subsets are critical to the protection of the host from various outside challenges. Epithelial surfaces, including the skin, serve as selective barriers where the immune system first encounters tissue-damaging radiation, toxins, mutagens, and various microorganisms. Studies in mice and humans have advanced the understanding of the integrated responses of T cells — including the major subsets defined by their TCR usage, alphabeta and gammadelta — and their relationship to other lymphoid cells, such as natural killer (NK) and natural killer T (NKT) cells. Parallel to the mechanisms that enable protective immune effects, misdirected and/or excessive activities of lymphoid cells may result in autoimmune or inflammatory disease states. Fortunately, cells with a regulatory function help to maintain immunologic balance. It is within this context that the crucial roles played by gammadelta T cells are increasingly being understood, an effort aided in large part by studies with mice in which the TCRdelta locus has been genetically disrupted (that is, TCRdelta-/- knockout mice) and no gammadelta T cells are present. Studies of skin cancer and contact dermatitis in these and other genetic variants have shed new light on the functions of gammadelta T cells, their relationship to other lymphoid cells, and the implications of such for the understanding of immune surveillance in human skin. Likewise, studies of murine gammadelta T cells have elucidated their similarities and differences relative to the more populous alphabeta T cells (Table 1).

For all four TCR loci (alpha, beta, gamma, and delta), the recombination of variable (V), diversity (D; for beta and delta chains), and junctional (J) region sequence elements (Table 2) generates a vast degree of TCR diversity (reviewed in Janeway et al., 2001), similar to the generation of B-cell antibody diversity via recombination of heavy and light chains. Within the area of the V(D)J joins — what is referred to as the complementarity-determining region 3 (CDR3) — additional variability may be introduced via random nucleotide insertion and/or deletion. It is the CDR3 that encodes the hypervariable TCR loops of antigen recognition. Though the basic heterodimeric structure of alphabeta and gammadelta TCRs is similar, there are several key differences in their array of genetic elements, the nature of their recombination, and their ultimate diversity. For example, there are far more V elements that may be utilized in alpha and beta gene rearrangements; nevertheless, gammadelta TCRs have a greater potential diversity because of their capacity to use multiple tandem copies of their D elements. A detailed analysis of CDR3 length (Rock et al., 1994) revealed that TCR alpha- and beta-chain distributions are highly constrained, doubtless because of structural requirements enabling binding and recognition of antigenic peptide within major histocompatibility complex (MHC) molecules. In contrast, TCRdelta chains are highly variable in length, resembling antibody heavy chain in this manner. This finding is consistent with the understanding that gammadelta TCRs have antigen recognition properties fundamentally different from those of alphabeta TCRs and likely bind their respective antigens in a fashion similar to that of antibodies (that is, independent of MHC presentation, and in a fashion more dependent on conformational shape of intact protein or non-protein compounds) (Table 3).


Tissue Distribution and Major Subsets of big gammadelta T Cells

Most T cells express TCRalphabeta and either of the TCR-associated molecules CD4 and CD8 on their surface, but a minority (1–10%) demonstrates a TCRgammadelta+, predominantly CD4-CD8- 'double-negative' phenotype. In the mouse, a substantial proportion of gammadelta T cells reside in the intraepithelial lymphocyte (IEL) compartments of skin, intestine, and genitourinary tract. Within the fetal thymus, precursors for these gammadelta T cells emerge in successive waves, guided to their respective tissues by the loss and gain of appropriate chemokine receptors. Vgamma5Vdelta1+ T cells are the first to leave the mouse fetal thymus and take residence in the suprabasal epidermis, forming a dendritic network that is unique among T cells but similar to that of Langerhans cells, the antigen-presenting cells of the epidermis. In physiologic states, these Vgamma5+ dendritic epidermal T cells (DETCs) constitute more than 90% of the epidermal T cells, with virtually no TCR diversity (Bergstresser et al., 1985). No phenotypically equivalent gammadelta+ IEL population has been identified in human epidermis, but gammadelta+ T cells of limited diversity and distinct from the peripheral blood gammadelta T-cell populations clearly reside within the dermis (Holtmeier et al., 2001). Characterization of these cells and their role in local immune responses awaits further investigation.

Several studies have demonstrated that the TCR expressed by the IEL population directs the association with the particular epithelial tissue. For example, developing DETCs demonstrate a more diverse set of gammadelta TCRs in the neonatal period, and these become much more uniform over the first few weeks of life (Tigelaar and Lewis, 1995). Eventually, in a manner analogous to that of Vgamma5 DETCs, other gammadelta T-cell subsets of limited TCR diversity are restricted to other epithelial tissues (for example, Vgamma6+ T cells in the genitourinary tract, Vgamma7+ T cells in the intestinal tract) (Itohara et al., 1989; Asarnow et al., 1989). This strongly suggests that a set of corresponding self-ligands is present in fetal and/or neonatal epithelia. Although no such set of IEL TCR-specific epithelial ligands has yet been definitively identified, several investigators have suggested that they may be expressed within the fetal thymus (allowing positive selection), as well as within each fetal/neonatal epithelium (allowing homing, peripheral selection, and expansion), but subsequently only on stressed or dysregulated epithelial cells (Janeway et al., 1988; Allison and Havran, 1991).

This hypothesis would be consistent with the paradigm that gammadelta IELs play a large role in protection of epithelial barriers via monitoring and appropriate destruction of stressed (that is, dysregulated, metabolically compromised, and/or transformed) epithelial cells (Pardoll, 2001). In the skin, DETCs may additionally promote wound healing, effectively protecting the barrier from microbial invasion and dissemination throughout the organism (Jameson et al., 2002). Additionally, gammadelta T cells may be important in helping to regulate inflammatory responses stimulated by alphabeta T cells, protecting against overly exuberant immune responses that might otherwise cause excessive tissue damage. Thus, an improved understanding of gammadelta T cells and their relationships to the skin has major implications for an improved understanding of cutaneous malignancy, infection, and inflammatory disease.

In the human fetal thymus, the first gammadelta T cells to emerge use the Vdelta1 chain (paired with various Vgamma chains), and these will eventually preferentially populate epithelial tissues such as the intestine (Hayday et al., 2001). Thus, whereas such Vdelta1+ T cells constitute only a minor proportion of the gammadelta T cells present in human blood, they constitute a much larger proportion of the human IELs and have also been found to be enriched within various human epithelial tumors (for example, lung, kidney, and colon carcinomas) and lymphomas (Fisch et al., 1997). Vdelta1 T cells appear to recognize stressed cells via presentation of self-lipids by CD1 and/or expression of stress-induced MHC-Ib molecules. In contrast, Vgamma9Vdelta2 T cells (also referred to as Vgamma2Vdelta2; for nomenclature, see Kabelitz and Wesch, 2003) continually expand and take on a memory phenotype during childhood, presumably because of recurrent exposure to foreign agents, such that they eventually constitute approximately 80% of the gammadelta T cells of normal adult human blood. These cells will recognize, expand, and release cytokines in response to non-peptide compounds found across a spectrum of microbial pathogens as well as within mammalian cells.

The immune system has classically been divided into two major arms: the more evolutionarily primitive innate immune system, where cell receptors and molecules may recognize and permit a rapid beneficial response to a variety of foreign agents, and the adaptive immune system, where B and T cells with antigen-specific receptors will produce a slower but more specific and coordinated initial immune response while also leading to expansion and a memory phenotype ready for subsequent challenges by the same antigen. One on hand, gammadelta T cells may be considered a component of the adaptive immune system in that they rearrange TCR genes to produce junctional diversity and will develop a memory phenotype. However, the various subsets may also be considered part of the innate immune system, where a restricted TCR may be used as a pattern recognition receptor. For example, according to this paradigm (Holtmeier and Kabelitz, 2005), large numbers of memory Vgamma9Vdelta2 T cells will respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vdelta1 T cells will respond to stressed epithelial cells bearing sentinels of danger. Clearly, the complexity of gammadelta T-cell biology spans definitions of both innate and adaptive immune responses.


Antimicrobial Immunosurveillance by big gammadelta T Cells

A range of studies have demonstrated a marked expansion of gammadelta T cells in the blood of systemically infected patients, including those with leprosy, tuberculosis, malaria, tularemia, salmonellosis, brucellosis, ehrlichiosis, or bacterial meningitis due to Haemophilus influenzae, Neisseria meningitidis, or Streptococcus pneumoniae (reviewed in Chen and Letvin, 2003). The broad recognition of the response may be the direct result of Vgamma9Vdelta2 stimulation by one of two major sets of shared non-peptide compounds: isopentenyl pyrophosphate and other intermediates of the mevalonate pathway; and alkylamines, non-phosphate compounds ubiquitously found in plants and bacteria (reviewed in Holtmeier and Kabelitz, 2005). In fact, the most potent natural stimulator of Vgamma9Vdelta2 T cells appears to be (E)-4-hydroxy-3-methylbut-2-enyl diphosphate, one of the precursors of isopentenyl pyrophosphate synthesis. Importantly, phosphoantigens are found expressed on many human tumor cells, possibly reflecting their state of raised metabolic stress, and will stimulate secretion of cytotoxic molecules by Vgamma9Vdelta2 cells (Bonneville and Fournie, 2005). Synthetic aminobisphosphonate compounds (for example, the drug pamidronate) also stimulate Vgamma9Vdelta2 cells, but this is more likely due to their stimulation of farnesyl diphosphate synthetase, which leads to accumulation of isopentenyl pyrophosphate. Studies are ongoing to identify potential immunostimulatory phosphoantigen drugs that might be therapeutic against malignancy (Wilhelm et al., 2003; Lozupone et al., 2004; Liu et al., 2005) and/or infection (Wang et al., 2001).

Human peripheral Vgamma9Vdelta2 cells, after their exposure to foreign infectious agents or dying or metabolically stressed host cells (for example, in tumor states), may enhance other immune components as well. Through the rapid secretion of chemokines and T helper 1 cytokines such as IFN-gamma, Vgamma9Vdelta2 cells may stimulate NK, NKT, and alphabeta T-cell functions (Smith and Hayday, 2000). Moreover, Brandes et al. (2005) recently discovered that Vgamma9Vdelta2 cells can also function as professional antigen-presenting cells capable of ingesting, processing, and presenting peptide antigens to stimulate both CD4+ and CD8+ subsets of alphabeta T cells. These findings collectively describe a scenario whereby Vgamma9Vdelta2 cells may be very early responders to states of infection or host cellular dysregulation, providing direct cytotoxic effects, altering the local cytokine/chemokine milieu to facilitate other lymphoid cells and initiating antigen-specific alphabeta T-cell immune responses through their capacity to function as APCs much like dendritic cells (Brandes et al., 2005).


Antitumor Immunosurveillance by big gammadelta T Cells

Within human epithelial compartments, gammadelta T cells, most notably gut Vdelta1+ T cells, may express surface NKG2D, a molecule found on two other major subsets of cells with cytotoxic potential, namely CD8+ alphabeta T cells and NK cells. Engagement of NKG2D by one of its several identified ligands, including MHC class I chain-related A and B (MICA and MICB) in humans (Bauer et al., 1999) and retinoic acid early-1 (Rae-1) in mice (Cerwenka et al., 2000), provides a co-stimulatory function and targets cellular destruction. These molecules are upregulated under cellular stress and are expressed on a variety of tumor cells (Groh et al., 1999), including melanoma (Vetter et al., 2002). They may act as signals that target host cells for destruction by locally resident or infiltrating gammadelta T cells as well as other NKG2D+ lymphoid cells. When the prototypic gammadelta IELs of mouse skin, the Vgamma5+ DETCs, are co-cultured with a keratinocyte tumor line expressing the NKG2D ligand Rae-1, the transformed cells are lysed, and such killing is dependent on TCR engagement (Girardi et al., 2001).

More recently, the relative contributions of alphabeta and gammadelta T cells to cutaneous tumor immunosurveillance have been systematically studied in mice (Girardi et al., 2001; Girardi et al., 2003b; Gao et al., 2003; Girardi et al., 2004). Intradermal injection of the mutagen methylcholanthrene can provoke the development of poorly differentiated fibrosarcomas and spindle-cell carcinomas. This occurs with shorter latency in TCRdelta-/- mice. Similarly, tumors form more readily in gammadelta-deficient mice after injection of squamous-cell carcinoma (Girardi et al., 2001) or melanoma (Gao et al., 2003) tumor cell lines. In addition to the potential of gammadelta T cells to directly lyse transformed cells in an NKG2D-dependent fashion, infiltrating gammadelta T cells have also been shown to produce IFN-gamma early in tumor development (Gao et al., 2003).

The concept that the different T-cell compartments may contribute to tumor surveillance in distinct fashions and at different stages of tumor growth has been further explored in the system of two-stage chemical carcinogenesis (where tumor development may be monitored after a single application of the mutagen 7,12-dimethylbenz[a]anthracene to the skin followed by repeated application of the tumor-promoting agent D12-O-tetradecanoylphorbol-13-acetate) (Hennings et al., 1993; Owens et al., 1999). In this system, benign papillomas readily develop and can progress to squamous-cell carcinoma. In TCRdelta-/- mice, both the development of papillomas and the progression to carcinoma were significantly increased (Girardi et al., 2001). This result, revealing that gammadelta T cells not only inhibit the early stages of tumor development but also limit progression to carcinoma, is consistent with the use of two or more different antitumor mechanisms by gammadelta T cells.

Further insight was provided by studies in TCRbeta-/- mice, which lack alphabeta T cells. Under an intense regimen of chemical promotion, tumors were significantly less likely to progress to carcinoma than in normal controls. This indicated a paradoxical tumor-promoting effect attributable to alphabeta T cells, an observation made in several other experimental cancer systems (Coussens and Werb, 2001). The findings also suggested that gammadelta T cells may downregulate potentially tumor-promoting alphabeta T cells (see below). In summary, mouse studies have elucidated three different pathways by which gammadelta T cells may provide anticancer activities: (1) direct killing of transformed cells, (2) early IFN-gamma production, and (3) a critical immunoregulatory mechanism. Thus, the antitumor role attributable to gammadelta T cells in the skin may be viewed as a component of a larger function of immunosurveillance and protection of the epidermal barrier (Figure 1).

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact or the author

Immunosurveillance by bold gammadelta T cells in murine skin. According to this model, gammadelta T cells would recognize damaged keratinocytes (KCs) as those cells displaying the (yet unidentified) TCR ligand as well as ligands for NKG2D (for example, retinoic acid early-1 (Rae-1)). Such cells can be rapidly eliminated via secretion of granzymes and perforin. Concurrently, gammadelta T cells may promote 'microscopic wound healing' through the release of fibroblast growth factor-VII (FGF-VII; keratinocyte growth factor-1) and IGF-1 (Sharp et al., 2005), stimulating lateral healthy keratinocytes to proliferate and fill in the voids. The secretion of anti-inflammatory compounds, as has been described for the lymphoid form of thymosin-beta4 (L-Tbeta4) (Girardi et al., 2003a), would also protect the epidermal barrier from the damaging effects of oxidative mediators released by neutrophils. Furthermore, the local secretion of IFN-gamma by gammadelta T cells (Gao et al., 2003) would enhance the antimicrobial, antitumor, and other functional activities of natural killer (NK) and alphabeta T cells, thus maintaining epidermal integrity.

Full figure and legend (38K)Download PowerPoint slide (119 KB)


T Regulatory Function by Dendritic Epidermal T Cells and Other big gammadelta T Cells

The observation that gammadelta T cells express certain chemokines and other regulatory molecules characteristic of T regulatory cells is consistent with the findings that immune responses to several pathogens (for example, intestinal Eimeria, Listeria monocytogenes, Mycobacterium tuberculosis, and Klebsiella) are not appropriately regulated in gammadelta-deficient mice (Roberts et al., 1996; Mombaerts et al., 1993; Mukasa et al., 1998; D'Souza et al., 1997). TCRdelta-/- mice have also shown accelerated immune responses in non-infectious settings, most notably the MRL/lpr model of lupus erythematosus (Peng et al., 1996) and an experimental model of epidermal autoimmunity mediated by alphabeta T cells (Shiohara et al., 1996). Strikingly, in the absence of gammadelta T cells, certain strains of mice will develop a spontaneous, alphabeta T cell-dependent dermatitis, as well as augmented responses to contact allergens and irritants (Girardi et al., 2002). The selective repopulation of TCRdelta-/- mice with Vgamma5+ DETCs by neonatal transfer with fetal thymic DETC precursors abrogates the augmented dermatitis, thus demonstrating that the resident gammadelta T cells provide a local T regulatory function. Additionally, these findings raise the possibility that IELs might exhibit a T regulatory function for systemic responses in other epithelial sites, including the intestine. This would be consistent with reports that IEL deficiencies are associated with human inflammatory bowel disease pathologies (Van Damme et al., 2001).

The mechanisms by which IELs may downregulate inflammatory responses in epithelia are beginning to be elucidated (Pennington et al., 2005). For example, gammadelta+ IELs and DETCs express high levels of thymosin-beta4 (Girardi et al., 2003a). Thymosin-beta4 is found within all cells, but, consistent with its function in actin sequestration, the oxidized form is a potent anti-inflammatory agent (Young et al., 1999). Moreover, activated gammadelta+ T cells express high levels of an alternate spliced version known as lymphoid thymosin-beta4. Consistent with the observation that lymphoid thymosin-beta4 contains an extra methionine that is readily oxidized, this splice variant was shown in vivo to be particularly anti-inflammatory in the skin (Girardi et al., 2003a). Nevertheless, a range of other possible activities may be operative, including expression of Fas ligand by gammadelta T cells, induction of Fas ligand on keratinocytes and secretion of cytokines such as transforming growth factor-beta and IFN-gamma (reviewed in Pennington et al., 2005).


big gammadelta T Cells in Human Disease

The study of gammadelta T cells in mice has increased our understanding of these cells in the human, including their propensity for epithelial surfaces and their multidimensional immune effects. The absence of a precise phenotypic DETC homologue in human skin suggests that functional equivalents must be operative. Whether these are provided by human dermal gammadelta T cells, infiltrating peripheral gammadelta T cells, alphabeta T cells, and/or NK cells is being explored. Nevertheless, studies of the ligand systems used by murine gammadelta T cells, and the exploration of their parallel activities mediated by human gammadelta T cells as well as other lymphoid populations, are likely to continue to provide insight into immunosurveillance and immune regulation in human disease.

As discussed above, DETCs constitutively express NKG2D, which recognizes the MHC-Ib molecules Rae-1 and H60 that are induced by skin chemical carcinogens. Human NKG2D+ cells similarly recognize stress-induced MICA and MICB on a myriad of solid tumors (Pardoll, 2001). The importance of NKG2D and its ligands in tumor recognition and elimination is increasingly being recognized. For example, the avoidance of recognition by NKG2D+ cells has been elucidated as a mechanism of tumor-driven immune evasion (Groh et al., 2002). Hence, it is crucial to clarify in humans which NKG2D+ cells actively mount an antitumor response, and to investigate potential means by which tumors may evade this attack (Oppenheim et al., 2005). Correspondingly, one major issue yet to be fully clarified in mouse gammadelta T-cell biology is the nature of the TCR ligands of DETCs and other gammadelta IELs, which represent a putative set of epithelium-specific danger signals. Once these TCR ligands are identified, the role of these molecules in epithelial homeostasis, tumor immunosurveillance, and regulation of inflammatory responses might be elucidated experimentally and correlated to human disease, in which novel therapeutic inroads may be made.

Furthermore, important strides continue to be made to explore the potential utility of human gammadelta T-cell subsets in immunotherapy protocols. Dendritic cell-based strategies, for example, target the adaptive immune system, providing peptide-antigen presentation and co-stimulatory molecules that may induce antigen-specific antitumor immunity. However, this may lead to editing of the tumor population with selection of those tumor cells that have altered their expression of tumor antigens, antigen-processing machinery, or MHC-presenting molecules (Dunn et al., 2004). Thus, complementary or integrative strategies are necessary. The phosphoantigen-mediated stimulation and expansion of Vgamma9Vdelta2 peripheral T cells represents a source of autologous cells with the capacity to kill a variety of tumor cells independently of MHC presentation of peptide antigen (Morita et al., 2001; Bonneville and Fournie, 2005).

As mentioned previously, gammadelta T cells have features of both innate and adaptive immunity and may serve critical roles in bridging these types of responses. The recent identification of the capacity of Vgamma9Vdelta2+ T cells to function as APCs (Brandes et al., 2005) adds yet another layer of complexity to our understanding of gammadelta T-cell biology. Brandes and colleagues demonstrated that, like dendritic cells, Vgamma9Vdelta2+ T cells can express co-stimulatory molecules and present conventional peptide antigens for the primary stimulation of CD4+ and CD8+ alphabeta T-cell responses. Hence, Vgamma9Vdelta2+ T cells may provide the ultimate link of innate and adaptive immunity by rapid expansion and secretion of cytokines (for example, through recognition of isopentenyl pyrophosphate, IPP, and (E)-4-hydroxy-3-methylbut-2-enyl diphosphate, MHB-PP) within hours of any encounter with pathogenic organisms, and by processing and presentation of foreign peptide to prime antigen-specific alphabeta T cells and coordinate a dual, innate and adaptive, immune response. As a potential avenue of gammadelta T-cell immunotherapy, it may ultimately prove possible to use peripheral gammadelta T cells in antitumor protocols in which such cells are activated and exposed to tumor antigen and thus may serve a dual role of stimulating both gammadelta T cell-directed antitumor activity and tumor antigen-specific CD4 and CD8 alphabeta T-cell responses.


Conflict of Interest

The author states no conflict of interest.



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