The biological role of IL-7Ralpha Y449 signaling in lymphocyte development, function and transformation

The cytokine interleukin (IL)-7 is necessary for human T cell development and murine B and T lymphopoiesis. Mice lacking IL-7, either of its receptor components, the common γ chain (γc) or IL-7 receptor α (IL-7Rα), or essential intracellular signaling molecules are severely lymphopenic. Due to the developmental block in early T and B progenitors, the requirement for IL-7Rα signaling in later T and B cell stages has been difficult to evaluate. To address this question, we characterized lymphopoiesis in IL-7Rα449F mice harboring a single point mutation in IL-7Rα, where a key signaling residue (tyrosine 449) is mutated to phenylalanine (F). Biochemical analysis revealed that IL-7Rα Y449 is essential for activation of STAT5 and that there are both Y449-dependent and independent contributions to cell survival through regulation of Bcl-2 family members. IL-7Rα449F T and B cells are able to overcome the characteristic developmental block of IL-7Rα-/- mice and develop appreciable numbers of peripheral T and B cells. This finding permitted evaluation of peripheral T cell function. These experiments demonstrated that IL-7Rα Y449 signals are required for naïve T cell homeostasis, generation of a primary CD4 T cell response and for maintenance of memory CD8 T cells following Listeria monocytogenes infection. In contrast to expectations, the CD8 memory T cell maintenance defect does not appear to be a direct result of decreased Bcl-2 expression. Dysregulated cytokine signaling can also contribute to development and/or maintenance of leukemia and lymphoma. Through genetic analysis of two distinct oncogenes, we were able to show that the IL-7Rα449F mutation was sufficient to protect mice from IL-7 mediated T and B cell transformation and significantly delay the emergence of B cell lymphomas in the Eμ-myc mouse model of Burkitt’s lymphoma. Disruption of STAT5 activation appears to play a significant role in both models of tumor protection. Collectively, the data demonstrate that IL-7Rα signaling has both Y449-dependent and independent modalities that cooperate to ensure optimal B and T cell development and response to infection. Further, the data show that these signaling pathways can contribute to lymphomagenesis, and may be attractive targets for immunotherapeutics of IL-7 responsive tumors.Science, Faculty ofMicrobiology and Immunology, Department ofGraduat