CD1d-restricted NKT cell activation enhanced homeostatic proliferation of CD8+ T cells in a manner dependent on IL-4

CD1d-restricted NKT cells are activated by TCR-mediated stimulation via CD1d plus lipid antigens such as alpha-galactosylceramide (alpha-GaICer). These cells suppressed autoimmunity and graft rejection, but sometimes enhanced resistance to infection and tumor immunity. This double-action phenomenon of NKT cells is partly explained by cytokines produced by NKT cells. Therefore, roles of cytokines from activated NKT cells have been extensively examined; however, their roles on T cell homeostatic proliferation in lymphopenic condition have not been investigated. Here, we showed that alpha-GaICer enhanced homeostatic proliferation of CD8(+) but not CD4(+) T cells and this effect of alpha-GaICer was required for NKT cells. IL-4 was essential and sufficient for this NKT cell action on CD8(+) T cell homeostatic proliferation. Importantly, the expression of IL-4R alpha and STAT6 in CD8(+) T cells was essential for the NKT activity, indicating a direct action of IL-4 on CD8(+) T cells. Consistent with this, the level of IL-4R alpha expression on memory phenotype CD8(+) T cells was higher than that on naive phenotype one and CD4(+) T cells. Thus, these results showed the 'involvement' of IL-4 that is produced from activated NKT cells for CD8(+) T cell homeostatic proliferation in vivo.