Editorial: “Recent advances in gamma/delta T cell biology: new ligands, new functions, and new translational perspectives”

Abstract

Since their discovery in the mid-1980s, interest in the immunological significance of γδ T cells has been subject to oscillations. The initial excitement over the unexpected discovery of a second T cell receptor (TCR) was followed by years of uncertainty as to the biological importance of these ambivalent T cells. Major breakthroughs led to the identification of specific and unique antigens for the γδ TCR and accumulating evidence now shows that γδ T cells play a major role in local immunosurveillance, thereby controlling tumorigenesis. Since 2004, biannual international γδ T cell conferences are held to bring together experts in basic and clinical γδ T cell research. To make accessible and synthesize the body of knowledge that has been put together, to date, we have organized a “Research Topic” on γδ T cells consisting of a collection of original articles and focused reviews written by leading experts in the field. The idea of this Research Focus was to present the current status and “hot topics” as well as clinical perspectives on γδ T cell research. The signaling pathways governing γδ T cell differentiation and activation have been discussed in contributions from Carl Wares’s (1) and Bruno Silva-Santos’s (2) groups. Ribeiro et al. discuss the control of γδ T cell activation and differentiation by distinct classes of cell surface receptors, namely (i) the TCR, (ii) costimulatory receptors (with a focus on CD27), (iii) cytokine receptors, (iv) NK receptors, and (v) inhibitory receptors. They further summarize how activation of γδ T cells can be controlled by the TCR as well as by activating NK receptors. To terminate γδ T cell responses, several inhibitory receptors can deliver negative signals, notably PD-1 and B- and T-lymphocyte attenuator (BTLA) (2). Bekiaris et al. focus on the cytokine control of innate γδ T cells, and discuss the role of IL-7 in being critical for thymic development of γδ T cells by regulating the survival of progenitor cells and inducing V(D)J recombination within the TCRγ gene locus. IL-7 also supports homeostatic proliferation of γδ T cells and regulates surface expression of BTLA in a STAT5-dependent manner (1). In recent years, IL-17 has been identified as an essential cytokine that regulates the recruitment of neutrophils during an inflammatory response. IL-17 must be rapidly available in an acute infection. αβ T cells producing IL-17 (Th17 cells) require specific antigenic stimulation and an appropriate cytokine milieu for differentiation. γδ T cells have been identified as an important “innate” source of rapid initial IL-17 production, which is thought to occur without specific TCR triggering (3). Several years ago, the group of Immo Prinz generated a unique mouse model to monitor early steps of γδ T cell development (4). Using these reporter mice, they demonstrated that IL-17 producing γδ T cells develop during the embryonic period and persist in adult mice as self-renewing, long-lived cells (5). Interestingly, Wei and colleagues have provided evidence that the TCR repertoire of such naturally occurring IL-17-producing murine γδ T cells is highly restricted, with little or no junctional diversity, regardless of their anatomical origin. These findings strongly suggest that antigen recognition is involved in the establishment and/or function of such “innate” IL-17 producing γδ T cells (6). Further aspects of IL-17 producing γδ T cells, also addressing their role in various pathophysiological conditions, are discussed in the review article by Patil et al. (7). In addition to production of cytokines, such as IL-17, γδ T cells can induce maturation of dendritic cells (DCs) and B cells. Petrasca and Doherty report on the upregulation of the expression of CD86, HLA-DR, IL-6, and TNFα in both DC and B cells upon coculture with human Vγ9Vδ2 T cells, whereas other cytokines, such as IFNγ or IL-4, were differentially induced in DC versus B cells (8). Collectively, their data indicate that γδ T cells can drive the expression of antigen presenting cell (APC)-associated markers in both DC and B cells (8). Interaction with neighboring cells is a key feature of γδ T cells. This is particularly true for tissue-resident γδ T cells. Witherden et al. have reviewed the multiple molecular interactions that have been characterized between skin-resident dendritic epidermal γδ T cells and keratinocytes. Among their many effector functions, epidermal γδ T cells are involved in wound repair, maintenance of epithelial homeostasis, and protection from malignant transformation (9). A final aspect of γδ T cell differentiation and plasticity is presented in the report of Ziegler et al. (10). These authors made the surprising observation that the small population of human peripheral blood Vδ1 γδ T cells that simultaneously express CD4, can differentiate into bona fide αβ T cells in a process called transdifferentiation. The authors took all measures to avoid the potential contribution of possible artifacts that may influence their results. Their characterization of human CD4⁺Vδ1 γδ T cells as a source of extrathymic T cell development challenges current dogmas and opens interesting avenues for future research (10). A particularly exciting new area of γδ T cell research is the role of butyrophilin and butyrophilin-like molecules (which consist of all members of the B7 family of co-stimulators) in γδ T cell activation. A member of this family, Skint-1, has been shown as critical...