IL-7 reverses NK1⁺ Tcell-defective IL-4 production in the non-obese diabetic mouse

Abstract

Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by the severe T lymphopenia observed in IL-7-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 cells 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+ T 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.

IL-18 Enhances IL-4 Production by Ligand-Activated NKT Lymphocytes: A Pro-Th2 Effect of IL-18 Exerted Through NKT Cells

“…It is therefore conceivable that, particularly in the diabetes model, the pro-Th2 effect of IL-18 treatment results from the capacity of IL-18 to promptly augment IL-4 production by NKT lymphocytes. Indeed, the implication of NKT cells in the control of the autoimmune disease in NOD mice was suggested by the demonstration of their reduced number and function (11,45) and by the prevention of diabetes observed after infusion of NKT cell preparations and in V␣14-J␣281-transgenic NOD mice (46,47).…”

Intrinsic Defects in the T-Cell Lineage Results in Natural Killer T-Cell Deficiency and the Development of Diabetes in the Nonobese Diabetic Mouse

“…It has been shown that IL-7, which is a product of thymic stromal cells, is required for the development and maturation of NKT cells (41,42). Exogenous IL-7 improved the IL-4 production of NOD thymocytes (43), suggesting defective NOD stromal cell functions.…”

Modulation of CD1d-restricted NKT cell responses by usingN-acyl variants of α-galactosylceramides

“…One example is the nonobese diabetic mouse. When compared with normal mice, nonobese diabetic mice have fewer V␣14i NKT cells, which are defective in their capacity to produce antiinflammatory cytokines like IL-4 (5,6). Deficiencies in NKT cells have also been observed in humans with various autoimmune diseases (7,8).…”