Invariant NKT cells inhibit development of the Th_(17) lineage

摘要

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 Thi 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 na?ve T cells we used an adoptive transfer model of traceable antigen-specific CD4Z~+ T cells. Transferred na?ve 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 na?ve T cells to the Th_(17) lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-y in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipu-lated 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 Jα18~(-/-) 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.