Functional dissection of the cytoplasmic subregions of the IL-2 receptor betac chain in primary lymphocyte populations.

The interleukin 2 (IL-2) receptor betac chain (IL-2Rbetac) is known to regulate the development and function of distinct lymphocyte populations. Thus far, the functions of the IL-2Rbetac cytoplasmic subregions have been studied extensively by using cultured cell lines; however, this approach has limitations with respect to their functions in distinct primary lymphocyte populations. In the present study, we generated mice each expressing a mutant form of an IL-2Rbetac transgene, lacking the cytoplasmic A- or H-region, on an IL-2Rbetac null background. We show that lack of the H-region, which mediates activation of the Stat5/Stat3 transcription factors, selectively affects the development of natural killer cells and T cells bearing the gamma delta T cell receptor. This region is also required for the IL-2-induced proliferation of T cells in vitro, by upregulating IL-2Ralpha expression. In contrast, the A-region, which mediates activation of the Src family protein tyrosine kinase (PTK) members, contributes to downregulation of the T cell proliferation function. The IL-2Rbetac null mutant mice develop severe autoimmune symptoms; these are all suppressed following the expression of either of the mutants, suggesting that neither the Stats nor the Src PTK members are required. Thus, our present approach offers new insights into the functions of these cytoplasmic subregions of the IL-2Rbetac chain.