Invariant NKT cells inhibit development of the Th₁₇ lineage
2009
Mars, Lennart T. | Araujo, Luiza | Kerschen, Philippe | Diem, Séverine | Bourgeois, Elvire | Van, Linh Pham | Carrié, Nadège | Dy, Michel | Liblau, Roland S. | Herbelin, André
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 Th₁ and Th₂ responses. Recently, a new subset of CD4⁺ T helper cells, called Th₁₇, was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4⁺ T cells. Transferred naïve CD25⁻CD62L⁺ CD4⁺ T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th₁₇ differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th₁₇ lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-γ 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 Th₁₇ response in mice lacking iNKT cells. This invigorated Th₁₇ response reverts to physiological levels when iNKT cells are introduced into Jα18⁻/⁻ mice by adoptive transfer, indicating that iNKT cells control the Th₁₇ compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th₁₇ lineage and suggest that iNKT cells provide a natural barrier against Th₁₇ responses.
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