Memory T cell homeostasis in humanized mice

Immunological memory is a key component of the adaptive immune system and provides long-lasting immunity against recurrent infections. Following clearance of viral infections, a pool of virus-specific memory T cells is generated and persists for a prolonged period of time. Recently, cytokine-producing cells in the bone marrow have been suggested to play a key role in the survival of memory T cells. However, the exact role and spectrum of cytokine-producing cells in the bone marrow, in particular their impact on human memory T cell survival, differentiation and function in vivo has not been elucidated. To address these questions we will use human cytokine/MHC knock-in reporter mice. Thus we will be able to analyze which CD4+ and CD8+ memory T cell subsets are in contact with which type of cytokine-producing cell in the bone marrow. Moreover, we will address the impact of the cytokine environment on migratory characteristics, survival and functional differentiation of human memory T cells in vivo. The human cytokine/MHC knock-in reporter mice will also allow us to analyze human memory T cell generation in vivo following human influenza vaccination and influenza virus infection, respectively. Taken together, this proposal will expand our knowledge of how the cytokine environment in the bone marrow affects human memory T cells in vivo by using human cytokine/MHC knock-in reporter mice. In addition, the characterization of human T cell responses in vivo upon challenge with antigen in human cytokine/MHC knock-in mice will represent a milestone towards the utility of humanized mice for preclinical vaccine testing and to study human immune responses in vivo.