Searching for “signal 2”: costimulation requirements of γδ T cells

T cell activation requires the integration of signals that arise from various types of receptors. Although TCR triggering is a necessary condition, it is often not sufficient to induce full T-cell activation, as reflected in cell proliferation and cytokine secretion. This has been firmly demonstrated for conventional αβ T cells, for which a large panel of costimulatory receptors has been identified. By contrast, the area remains more obscure for unconventional, innate-like γδ T cells, as the literature has been scarce and at times contradictory. Here we review the current state of the art on the costimulatory requirements of γδ T cell activation. We highlight the roles of members of the immunoglobulin (like CD28 or JAML) or tumour necrosis factor receptor (like CD27) superfamilies of coreceptors, but also of more atypical costimulatory molecules, such as NKG2D or CD46. Finally, we identify various areas where our knowledge is still markedly insufficient, hoping to provoke future research on γδ T cell costimulation.