Invariant Nkt Cells Inhibit Development Of The Th-17 Lineage

T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th-1 and Th-2 responses. Recently, a new subset of CD4(+) T helper cells, called Th-17, was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naive T cells we used an adoptive transfer model of traceable antigen-specific CD4(+) T cells. Transferred naive CD25(-)CD62L(+) CD4(+) T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th-17 differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naive T cells to the Th-17 lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-gamma in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th-17 response in mice lacking iNKT cells. This invigorated Th-17 response reverts to physiological levels when iNKT cells are introduced into J alpha 18(-/-) mice by adoptive transfer, indicating that iNKT cells control the Th-17 compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th-17 lineage and suggest that iNKT cells provide a natural barrier against Th-17 responses.