IL-7 Up-Regulates IL-4 Production by Splenic NK1.1+ and NK1.1− MHC Class I-Like/CD1-Dependent CD4+ T Cells

NK T cells are an unusual subset of T lymphocytes. They express NK1.1 Ag, are CD1 restricted, and highly skewed toward Vβ8 for their TCR usage. They express the unique potential to produce large amounts of IL-4 and IFN-γ immediately upon TCR cross-linking. We previously showed in the thymus that the NK T subset requires IL-7 for its functional maturation. In this study, we analyzed whether IL-7 was capable of regulating the production of IL-4 and IFN-γ by the discrete NK T subset of CD4+ cells in the periphery. Two hours after injection of IL-7 into mice, or after a 4-h exposure to IL-7 in vitro, IL-4 production by CD4+ cells in response to anti-TCR-αβ is markedly increased. In contrast, IFN-γ production remains essentially unchanged. In β2-microglobulin- and CD1-deficient mice, which lack NK T cells, IL-7 treatment does not reestablish normal levels of IL-4 by CD4+ T cells. Moreover, we observe that in wild-type mice, the memory phenotype (CD62L−CD44+) CD4+ T cells responsible for IL-4 production are not only NK1.1+ cells, but also NK1.1− cells. This NK1.1−IL-4-producing subset shares three important characteristics with NK T cells: 1) Vβ8 skewing; 2) CD1 restriction as demonstrated by their absence in CD1-deficient mice and relative overexpression in MHC II null mice; 3) sensitivity to IL-7 in terms of IL-4 production. In conclusion, the present study provides evidence that CD4+MHC class I-like-dependent T cell populations include not only NK1.1+ cells, but also NK1.1− cells, and that these two subsets are biased toward IL-4 production by IL-7.