A key role of γδ T cells consists of discriminating between the host and pathogens by reacting rapidly towards non-peptide antigens following infection and thereby activating the innate immune cells and thus facilitating the adaptive immune responses of αβ T cells (Fig 1). Circulating Vδ2+ T cells are involved in the elimination of some microbial pathogens, such as intracellular bacteria (Mycobacterium tuberculosis, Francisella tularensis, Borrelia burgdorferi), parasites (Plasmodium falciparum) and viruses (HIV and Influenza A; Casetti et al, 2008; Spencer et al, 2008; Ali et al, 2009; Henry et al, 2010; Qin et al, 2011; Shi et al, 2011). Many studies have shown that γδ T cells play a role in bridging the innate and adaptive immune responses. They have provided evidence that Vδ2+ cells, like αβ T cells, can contribute to the adaptive immune response and the maintenance of the immune homeostasis and have immunoregulatory functions as well (Born et al, 2006; Girardi, 2006; Konigshofer & Chien, 2006; Moser & Eberl, 2007). Moreover, a recent work has revealed that, surprisingly, human γδ T cells share some properties with professional antigen-presenting cells (APCs), like DCs (Brandes et al, 2009; Himoudi et al, 2012). Indeed, upon activation, γδ T cells efficiently process and display antigens and provide co-stimulatory signals that are sufficient to strongly induce proliferation, differentiation, target cell killing and cytokine production by antigen-experienced and naive CD8+ αβ T cells (Meuter et al, 2010). In addition, Vγ9Vδ2 T cells that had been stimulated with IPP seemed to be more efficient in antigen cross-presentation than DCs derived from monocytes (Brandes et al, 2009; Fig 1). Interestingly, recent works described a novel minor (<1%) subset of human interleukin 17 (IL-17)-producing (IL-17+) Vγ9Vδ2 T cells in the peripheral blood of healthy donors or in mice that play a critical role in the inflammatory responses following bacterial infections and in anti-tumour responses (Lockhart et al, 2006; Sutton et al, 2009; Ribot et al, 2010; Hayes & Laird, 2012). Moreover, Caccamo et al (2011) reported that, in children with bacterial meningitis, IL-17+ Vγ9Vδ2 T cells could account for 60–70% of all the γδ T cells in blood and cerebrospinal fluid and that their concentration decreased after successful antibacterial therapy. IL-17+ Vγ9Vδ2 T cells were generated in vitro using T helper 17 (Th17)-polarizing culture conditions (a cocktail of transforming growth factor-β, IL-1β, IL-6, IL-23) followed by an additional week of expansion in IL-2–rich medium (Caccamo et al, 2011). In such conditions, IL-6 plays a crucial role in the generation of IL-17+ γδ T cells, differently from that described for both human Vγ9Vδ2 and mouse γδ T cells (Ribot et al, 2009). Thus, the work by Caccamo et al (2011) provided new important in vivo data on the physiological importance of IL-17+ Vγ9Vδ2 T cells and an in vitro approach to facilitate their study. It is now important to identify the components of the inflammatory niches in which IL-17+ Vγ9Vδ2 T cells accumulate in vivo.
Figure 1. Multiple functions of γδ T cells. (1) Following T cell receptor (TCR)-dependent activation, γδ T cells release perforin and granzymes, as an early step of their cytotoxic activity. (2) CD16+ effector γδ T cells bind to the Fc region of monoclonal antibodies that target tumour cells, thereby exercising their antibody-dependent cellular cytotoxicity (ADCC) function. (3) γ interferon (INFγ) and tumour necrosis factor α (TNFα) secretion by γδ T cells indicate their implication in immune defence/response networks. (4) Upon TCR engagement, Fas ligand (Fas-L) and TNF-related apoptosis-inducing ligand (TRAIL) expression is up-regulated in γδ T cells and as, a consequence, the Fas- or TRAIL-receptor (R) sensitive tumour cell killing by γδ T cells is enhanced. (5) Human γδ T cells can act as professional antigen-presenting cells because they can process and display antigens and can also provide co-stimulatory signals necessary for the induction of proliferation, differentiation and target cell killing. MHC, major histocompatibility complex.
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