François Machavoine

IL‐4‐producing NK T cells are biased towards IFN‐γ production by IL‐12. Influence of the microenvironment on the functional capacities of NK T cells

NK T cells are an unusual T lymphocyte subset capable of promptly producing several cytokines after stimulation, in particular IL‐4, thus suggesting their influence in Th2 lineage commitment. In this study we demonstrate that, according to the cytokines present in the micro environment, NK T lymphocytes can preferentially produce either IL‐4 or IFN‐γ. In agreement with our previous reports showing that their IL‐4‐producing capacity is strikingly dependent on IL‐7, CD4− CD8− TCRα β+ NK T lymphocytes, obtained after expansion with IL‐1 plus granulocyte‐macrophage colony‐stimulating factor, produced almost undetectable amounts of IL‐4 or IFN‐γ in response to TCR/CD3 cross‐linking. However, the capacity of these T cells to produce IFN‐γ is strikingly enhanced when IL‐12 is added either during their expansion or the anti‐CD3 stimulation, while IL‐4 secretion is always absent. A similar effect of IL‐12 on IFN‐γ production was observed when NK T lymphocytes were obtained after expansion with IL‐7. It is noteworthy that whatever cytokines are used for their expansion, IL‐12 stimulation, in the absence of TCR/CD3 cross‐linking, promotes consistent IFN‐γ secretion by NK T cells without detectable IL‐4 production. Experiments in vivo demonstrated a significant up‐regulation of the capacity of NK T cells to produce IFN‐γ after anti‐CD3 mAb injection when mice were previously treated with IL‐12. In conclusion, we provide evidence that the functional capacities of NK T cells, which ultimately will determine their physiological roles, are strikingly dependent on the cytokines present in their microenvironment.

Histidine Decarboxylase Deficiency Prevents Autoimmune Diabetes in NOD Mice.

Recent evidence has highlighted the role of histamine in inflammation. Since this monoamine has also been strongly implicated in the pathogenesis of type-1 diabetes, we assessed its effect in the nonobese diabetic (NOD) mouse model. To this end, we used mice (inactivated) knocked out for the gene encoding histidine decarboxylase, the unique histamine-forming enzyme, backcrossed on a NOD genetic background. We found that the lack of endogenous histamine in NOD HDC−/− mice decreased the incidence of diabetes in relation to their wild-type counterpart. Whereas the proportion of regulatory T and myeloid-derived suppressive cells was similar in both strains, histamine deficiency was associated with increased levels of immature macrophages, as compared with wild-type NOD mice. Concerning the cytokine pattern, we found a decrease in circulating IL-12 and IFN-γ in HDC−/− mice, while IL-6 or leptin remained unchanged, suggesting that histamine primarily modulates the inflammatory environment. Paradoxically, exogenous histamine given to NOD HDC−/− mice provided also protection against T1D. Our study supports the notion that histamine is involved in the pathogenesis of diabetes, thus providing additional evidence for its role in the regulation of the immune response.