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Doctoral Student Supervision (Jan 2008 - Nov 2019)
The cytokine Interleukin-7 (IL-7) is critical for T cell development and function. Mutations that block IL-7 signaling in humans cause severe combined immunodeficiency syndrome due to the failure of T cells to develop. Conversely, mutations that result in constitutive signaling through the IL-7 receptor can drive human leukemias, including Early Thymic Progenitor (ETP) acute lymphoblast leukemia. How IL-7 influences ETP development is still unclear since ETPs do not normally express IL-7Rα. We found that ETPs are highly dependent on and sensitive to changes in IL-7 signaling however, IL-7Rα expressing bone marrow progenitors are not. IL-7 does not regulate the survival or proliferation of ETPs, although it does at subsequent stages of T cell development. We hypothesize an instructive role of IL-7 signaling in the differentiation or migration of bone marrow precursors of ETPs that is distinct from its classic mechanisms regulating survival and proliferation.Adjuvant IL-7 has been shown to increase the quantity and quality of T cell responses to clear chronic viral infections, however, its physiological role in anti-viral T cells is unclear. We found that IL-7 signaling was required for efficient clearance of Influenza A virus (IAV) and protection from viral induced pathology. T cells require cell intrinsic IL-7 signaling for efficient primary CD4 and CD8 T cell responses to IAV. The requirement for IL-7 signaling in the anti-viral response, and the ability of exogenous IL-7 to boost T cell responses suggests that it may be clinically useful in therapy or vaccination against IAV. IAV remains an important global health challenge, with up to 10% of the global population infected annually. Current IAV vaccines do not generate universal cross-serotype immunity. T cell memory responses to IAV correlate with cross-serotype protection. Transcutaneous immunization has shown potential to induce memory T cell responses that can protect against infections at other mucosal sites, including the lung. We found that transcutaneous immunization generates a strong memory CD8 T cell response that can protect from challenge with IAV. Therefore, transcutaneous immunization may be a useful to produce cross-serotype IAV immunity.
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 mutationin 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.