Among immune cells, dendritic cells (DC) and invariant (i) NKT cells are critically implicated in allergic asthma. However, the interaction between two subsets remains elusive in asthma. To address this, we investigated how these two subsets interact and exert regulatory effects on asthma. Upon intranasal inoculation of WT mice with synthetic ligand, a-galactosyl ceramide (a-GalCer), CD103+ DCs were significantly recruited into the lungs in WT but not CD1d KO mice, suggesting that iNKT cells contribute to recruiting CD103+ DCs in the respiratory system. Moreover, microarray assay revealed that iNKT cells highly expressed XCL1, a chemokine for CD103+ DCs expressing XCR1. Consistently, a-GalCer treatment increased production of XCL1 by iNKT cells in vitro and in vivo, and XCL1 KO mice showed a deficiency in iNKT cell-mediated recruitment of CD103+ DCs into the lungs. In the OVA-induced allergic asthma model, XCL1 KO mice attenuated airway resistance, inflammation, CD103+ DC number, and Th2 type immune responses in the lungs. Furthermore, adoptive transfer of XCL1-deficient iNKT cells did not alter airway resistance and recruit CD103+ DCs in CD1d KO mice, whereas WT iNKT cells or CD103+ DCs restored allergic asthma. Taken together, this study demonstrates that iNKT cells crosstalk CD103+ DCs via XCL1-XCR1 axis, thereby promoting allergic asthma.
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 stimulation in a dose-dependent manner. Consistently, sodium chloride reduced the expression level of t-bet, but not gata-3, in iNKT cells stimulated with TCR engagement. Sodium chloride increased phosphorylated p38 expression in iNKT cells and inhibitors of p38 and NFAT5, and SGK1 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 upon TCR stimulation, which is dependent on p38, NFAT5, and SGK1. These findings highlight the functional role of sodium chloride in iNKT cell-mediated inflammatory diseases.
Long chain fatty acids (LCFAs) exert pro-inflammatory effects in vivo. However, little is known regarding the effect of LCFAs on invariant (i) NKT cell functions. Here, we report an inhibitory effect of saturated LCFAs on transcription factors in iNKT cell. Among the saturated LCFAs, palmitic acid (PA) specifically inhibited IL-4 and IFN-g production and reduced gata-3 and t-bet transcript levels in iNKT cells during TCR-mediated activation. In iNKT cells, PA was localized and induced dilation in the endoplasmic reticulum and increased the mRNA levels of downstream molecules of IRE1 RNase. Moreover, PA increased the degradation rates of gata-3 and t-bet mRNA, which were restored by IRE1 inhibition, indicating that gata-3 and t-bet are cleaved via regulated IRE1a-dependent decay (RIDD). A PA-rich diet suppressed IL-4 and IFN-g production by iNKT cells in wildtype mice, thereby attenuating arthritis. This study demonstrates that a saturated LCFA induced RIDD-mediated t-bet and gata-3 mRNA degradation in iNKT cells, thereby suppressing cytokine production.
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