Impaired T cell function and CD8 memory maintenance in a novel IL-7Rα knock-in mouse (B30)

Abstract

Abstract Interleukin (IL)-7 is an essential growth factor for thymocyte development and survival of peripheral T cells, specifically CD8+ memory T cells. Current models such as IL-7 or IL-7 receptor alpha (IL-7Rα) knock-out mice have demonstrated the necessity of IL-7 signaling in these processes, but are unable to delineate the involvement of downstream pathways. To more precisely identify signals governing IL-7 function in vivo, we have disrupted the IL-7Rα Y449XXM motif in mice by knock-in mutagenesis (IL-7Rα449F). Thymocytes from these mice overcome a double negative (DN) stage developmental block that allows subsequent T cell maturation and peripheral migration. This is in stark contrast to the severe cytopenia seen in IL-7Rα−/− mice. These findings highlight the importance of IL-7Rα Y449-mediated signals during thymopoiesis, but also indicate a requirement for Y449-independent signals. Infection of IL-7Rα449F mice with the intracellular pathogen Listeria monocytogenes revealed that CD4 and CD8 T cells had different requirements for IL-7Rα signals. Strikingly, CD4 T cells failed to mount a detectable primary response to Listeria. Despite normal CD8 primary responses, maintenance of Listeria-specific CD8 memory was impaired in IL-7Rα449F mice. Furthermore, we show that Bcl-2 is IL-7Rα Y449-independent and insufficient for IL-7-mediated maintenance of CD8 memory. Research funded by the Canadian Institutes of Health Research and the Michael Smith Foundation for Health Research