IL-7 reverses NK1(+) T cell-defective IL-4 production in the non-obese diabetic mouse

Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by the severe T lymphopenia observed in Il-l-deficient mice. We recently reported that IL-7 preferentially promotes the in vitro expansion of a discrete MHC class I-dependent lymphocyte subset comprising both CD4(+) and CD4(-)CD8(-) TCR alpha beta(+) cells bearing several NK cell markers such NK1.1 and Ly-49. These T cells, designated as NK1(+) T cells, have the unique property among thymocytes of producing large amounts of IL-4 upon primary stimulation via the TCR. We have further demonstrated that thymic NK1(+) T cells of non-obese diabetic (NOD) mice, a spontaneous model of autoimmune type I diabetes, are markedly deficient in maturation both quantitatively and functionally (IL-4 production). In the present experiments, the addition of exogenous IL-7 completely restored IL-4 production by anti-TCR alpha beta-stimulated mature (HSA(-)CD8(-)) thymocytes in NOD mice, A short 2 h preincubation with IL-7 was sufficient to restore both the expression of IL-4 mRNA and IL-4 production capacity. This was related to a direct effect on NK1(+) thymocytes since: (i) the effect of IL-7 was restricted to the non-mainstream MEL-14(-) 3G11(-) TCR alpha beta(+) subset which mostly concentrates the IL-4-producing capacity and (ii) IL-7 did not restore IL-4 production in class I-deficient mice which lack the NK1(+) T cell subset. Importantly, this activity of IL-7 on NK1(+) i cells was also demonstrated in non-autoimmune strains of mice. These results were extended in vivo by showing that the IL-7 treatment significantly increased the anti-CD3 triggered IL-4 production by NK1(+) T spleen cells. These findings confirm the role of IL-7 in NK1(+) T cell maturation and suggest that the NK1(+) T cell defect in NOD mice could be related to insufficient intrathymic IL-7 bioavailability.