Distinct regulation of autoreactive CD4 T cell expansion by interleukin-4 under conditions of lymphopenia

IL‐4 is protective against Type 1 diabetes in the NOD mouse. IL‐4 promotes T cell survival in vitro, but little is known about the effect of IL‐4 on clonal expansion in vivo. Here, we show that IL‐4 only enhances the expansion of autoreactive CD4 T cells during lymphopenia and that neither the presence of islet IL‐4 nor IL‐4 deficiency affects T cell expansion significantly under conditions of immunosufficiency. The accumulation of proliferating cells induced by IL‐4 in a lymphopenic host is inhibited incrementally by increasing the number of bystander cells and is prevented by cell numbers well below that of unmanipulated NOD mice. The ability of IL‐4 to promote autoreactive CD4 T cell expansion is therefore sensitive to the degree of host immunodeficiency. Paradoxically, IL‐4 receptor‐deficient, autoreactive CD4 T cells proliferate more extensively than wild‐type T cells in immunodeficient hosts, suggesting that the growth‐promoting effect of islet IL‐4 acts indirectly. These results suggest that IL‐4‐mediated protection against autoimmunity and diabetes may be outweighed during immunodeficiency by a pathogenic, IL‐4‐induced expansion of autoreactive T cells.