IL-7 REVERSES NK1(-CELL-DEFECTIVE IL-4 PRODUCTION IN THE NONOBESE DIABETIC MOUSE() T)

Converging data suggest an important role for IL-7 in T lymphocyte mat uration as illustrated by the severe T lymphopenia observed in Il-l-de ficient mice. We recently reported that IL-7 preferentially promotes t he in vitro expansion of a discrete MHC class I-dependent lymphocyte s ubset comprising both CD4(+) and CD4(-)CD8(-) TCR alpha beta(+) cells bearing several NK cell markers such NK1.1 and Ly-49. These T cells, d esignated as NK1(+) T cells, have the unique property among thymocytes of producing large amounts of IL-4 upon primary stimulation via the T CR. We have further demonstrated that thymic NK1(+) T cells of non-obe se diabetic (NOD) mice, a spontaneous model of autoimmune type I diabe tes, are markedly deficient in maturation both quantitatively and func tionally (IL-4 production). In the present experiments, the addition o f 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 expres sion 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 r estricted to the non-mainstream MEL-14(-) 3G11(-) TCR alpha beta(+) su bset which mostly concentrates the IL-4-producing capacity and (ii) IL -7 did not restore IL-4 production in class I-deficient mice which lac k the NK1(+) T cell subset. Importantly, this activity of IL-7 on NK1( +) i cells was also demonstrated in non-autoimmune strains of mice. Th ese results were extended in vivo by showing that the IL-7 treatment s ignificantly 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.