Thymic selection determines γδ T cell effector fate:: Antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon γ

gamma delta T cells uniquely contribute to host immune defense, but how this is accomplished remains unclear. Here, we analyzed the nonclassical major histocompatibility complex class I T10 and T22-specific gamma delta T cells in mice and found that encountering antigen in the thymus was neither required nor inhibitory for their development. But when triggered through the T cell receptor, ligand-naive lymphoid-gamma delta T cells produced IL-17, whereas ligand-experienced cells made IFN-gamma. Immediately after immunization, a large fraction of IL-17(+) gamma delta T cells were found in the draining lymph nodes days before the appearance of antigen-specific IL-17(+) alpha beta T cells. Thus, thymic selection determines the effector fate of gamma delta T cells rather than constrains their antigen specificities. The swift IL-17 response mounted by antigen-naive gamma delta T cells suggests a critical role for these cells at the onset of an acute inflammatory response to novel antigens.