Mechanisms of homeostatic peripheral T cell maintenance in the absence of the epigenetic regulator SETD1A.

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T cells are of great importance for immune competence conferring efficient responses against pathogens and tumor antigens. To this end diversity and size of the peripheral T cell pool is crucial for the instigation, intensity, and longevity of immune responses. Throughout the aging process, de novo production of T cells decreases, placing homeostatic mechanisms maintaining peripheral T cell numbers into the focus. Among other features, senescence and DNA damage are hallmarks of aging, and the epigenetic regulator SETD1A protects from either in cancer cells in vitro and in hematopoietic progenitor cells in vivo, respectively. We have identified SETD1A as the key histone methyltransferase in hematopoietic stem and progenitor cells in mice that controls the expression of components of virtually all DNA damage recognition and repair pathways. Using T cell specific CRE-recombinase deleter mice (CD4-Cre), we present here preliminary data pointing at a role for Setd1a in the maintenance of the peripheral T cell pool. Late stages of intrathymic T cell differentiation are not affected, thus, Setd1a is crucial specifically in peripheral T cells. Within this proposal we outline experiments aiming at uncovering mechanisms by which Setd1a controls the peripheral T cell pool size and explore the function of Setd1a in the context of age-associated phenotypes including immune senescence and lymphomagenesis.