Role of γδ T cells in α-galactosylceramide-mediated immunity

Attempts to harness mouse type I NKT cells in different therapeutic settings including cancer, infection, and autoimmunity have proven fruitful using the CD1d-binding glycolipid alpha-galactosylceramide (alpha-GalCer). In these different models, the effects of alpha-GalCer mainly relied on the establishment of a type I NKT cell-dependent immune cascade involving dendritic cell, NK cell, B cell, or conventional CD4(+) and CD8(+) T cell activation/regulation as well as immunomodulatory cytokine production. In this study, we showed that gamma delta T cells, another population of innate-like T lymphocytes, displayed a phenotype of activated cells (cytokine production and cytotoxic properties) and were required to achieve an optimal alpha-GalCer-induced immune response. Using gene-targeted mice and recombinant cytokines, a critical need for IL-12 and IL-18 has been shown in the alpha-GalCer-induced IFN-gamma production by gamma delta T cells. Moreover, this cytokine production occurred downstream of type I NKT cell response, suggesting their bystander effect on gamma delta T cells. In line with this, gamma delta T cells failed to directly recognize the CD1d/alpha-GalCer complex. We also provided evidence that gamma delta T cells increase their cytotoxic properties after alpha-GalCer injection, resulting in an increase in killing of tumor cell targets. Moreover, using cancer models, we demonstrated that gamma delta T cells were required for an optimal alpha-GalCer-mediated anti-tumor activity. Finally, we reported that immunization of wild-type mice with alpha-GalCer enhanced the adaptive immune response elicited by OVA, and this effect was strongly mediated by gamma delta T cells. We conclude that gamma delta T cells amplify the innate and acquired response to alpha-GalCer, with possibly important outcomes for the therapeutic effects of this compound. The Journal of Immunology, 2012, 188: 3928-3939