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During interaction with APCs, invariant ( i ) NKT cells are thought to be indirectly activated by TLR4-dependently activated APCs. However, whether TLR4 directly activates  i NKT cells is unknown. Therefore, the expression and function of TLR4 in  i NKT cells were investigated. Flow cytometric and confocal microscopic analysis revealed TLR4 expression on the surface and in the endosome of  i NKT cells. Upon LPS stimulation,  i NKT cells enhanced IFN-γ production, but reduced IL-4 production, in the presence of TCR signals, depending on TLR4, MyD88, TRIF, and the endosome. However, enhanced TLR4-mediated IFN-γ production by  i NKT cells did not affect IL-12 production or CD1d expression by DCs. Adoptive transfer of WT, but not TLR4-deficient,  i NKT cells promoted antibody-induced arthritis in CD1d −/−  mice, suggesting that endogenous TLR4 ligands modulate  i NKT cell function in arthritis. Furthermore, LPS-pretreated WT, but not TLR4-deficient,  i NKT cells suppressed pulmonary fibrosis, but worsened hypersensitivity pneumonitis more than untreated WT  i NKT cells, indicating that exogenous TLR4 ligands regulate  i NKT cell functions in pulmonary diseases. Taken together, we propose a novel direct activation pathway of  i NKT cells in the presence of TCR signals via endogenous or exogenous ligand-mediated engagement of TLR4 in  i NKT cells, which regulates immune diseases by altering IFN-γ and IL-4 production.

Direct Engagement of TLR4 in Invariant NKT Cells Regulates Immune Diseases by Differential IL-4 and IFN-γ Production in Mice