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Abstract: Invariant NKT (iNKT) cells are a distinct subset of T cells that exert Janus‐like functions in vivo by producing IFN‐γ and IL‐4. Sodium chloride modulates the functions of various immune cells, including conventional CD4+ T cells and macrophages. However, it is not known whether sodium chloride affects iNKT cell function, so we addressed this issue. Sodium chloride inhibited IFN‐γ, but not IL‐4, production by iNKT cells upon TCR or TCR‐independent (IL‐12 and IL‐18) stimulation in a dose‐dependent manner. Consistently, sodium chloride reduced the expression level of tbx21, but not gata‐3, in iNKT cells stimulated with TCR engagement or IL‐12 + IL‐18. Sodium chloride increased phosphorylated p38 expression in iNKT cells and inhibitors of p38, NFAT5, SGK1, and TCF‐1 restored IFN‐γ production by iNKT cells stimulated with sodium chloride and TCR engagement. Furthermore, adoptive transfer of iNKT cells pretreated with sodium chloride restored antibody‐induced joint inflammation to a lesser extent than for untreated iNKT cells in Jα18 knockout mice. These findings suggest that sodium chloride inhibits IFN‐γ production by iNKT cells in TCR‐dependent and TCR‐independent manners, which is dependent on p38, NFAT5, SGK1, and TCF‐1. These findings highlight the functional role of sodium chloride in iNKT cell‐mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]