IL-7R alpha signaling in the T cell response to Influenza

The development and maintenance of lymphocytes in mammals is a tightly regulated process involving the interplay of numerous cytokines, chemokines and growth factors. An effective immune response to infection by a pathogen involves an initiation and expansion phase, followed by contraction, generation and maintenance of memory cells. The cytokine Interleukin-7 (IL-7) is essential for development of pro-B and pro-T cells and normal function and survival of peripheral T cells. Loss of IL-7 or either component of its heterodimeric receptor, the IL- 7Ra, results in severe combined immunodeficiency in mice and T cell immunodeficiency in humans. IL-7 and its signaling capacity have been shown to be essential in maintenance and function of peripheral T cells. Conversely, over-expression of IL-7 in mice causes early mortality from lymphomas. The control of lymphocytes by IL-7 is an excellent model for analysis of key checkpoints in regulation and deregulation of primary and memory T cell function to elucidate potential therapeutic targets. The objective of this study is therefore to identify the requirement of IL-7Ra-induced signaling pathways for the development of the primary and secondary T cell response to Influenza virus, a microorganism highly pathogenic for humans, especially immunocomprimized and elderly people. A unique IL-7Ra mutant mouse model with a site-specific mutation of the cytoplasmic tyrosine Y449 will be used which allows, in contrast to conventional gene-targeted deletion strategies, the analysis on the role of IL-7 on the development and maintenance of T cell memory upon pathogen exposure. Wild-type and IL- 7Ra 449F mutant mice will be infected with Influenza A H3N2 and re-challenged with a serologically distinct Influenza H1N1 virus strain. Comprehensive functional studies after defined time intervals include multimer staining of Influenza-specific CD4 and CD8 T cell populations, cytokine production and phenotypical screening. The influenza-specific memory T cell maintenance after secondary challenge will be additionally characterized in respect of the cytotoxic potential, clonal composition and antigen avidity of responding virus-specific T cell populations as well as IL-7Ra-dependent signaling cascades. We will consider the possibility that IL-7Ra 449F T cells may have different properties influencing their responsibility to Influenza by evaluating Y449-dependent and -independent IL-7Ra-mediated signaling pathways. Furthermore, the role of Thymic Stromal Lymphopoietin (TSLP) in shaping the response to Influenza will be explored as this cytokine also uses the IL-7Ra chain in its biological actions. In doing so, we will determine IL-7 induced signals that are essential for immune responses and memory to Influenza, a virus which is characterized by high prevalence and pathogenicity in humans. We thereby expect novel insights into potential therapies for both vaccine design and lymphoid tumors and hope to significantly contribute to the development of better Influenza vaccine strategies.