Early-life hematopoiesis correlates with MHC-independent development of virtual memory T cells 3074

Abstract Description Major histocompatibility complex (MHC) molecules play a crucial role in the maturation of αβ T cells. However, we discovered a peculiar population of CD8 T cells expressing the αβ T cell receptor in MHC-deficient mice, which closely resembles virtual memory (VM) T cells in phenotype, transcriptomic profile, and function. This finding showed that VM T cells can develop independently of MHC. To investigate the mechanism underlying this MHC-independent development, we used a mouse model that enables the tracking of CD8 T cells developed at specific life stages. We found that VM T cells developed without MHC share greater phenotypic and transcriptional similarity with VM T cells originating in early life. Consistent with wild-type observations, analysis of the neonatal thymus in MHC-deficient mice revealed a temporal expression of Lin28b, a master regulator of fetal hematopoiesis, in CD4-CD8- (DN) thymic progenitors during early life. This was accompanied by the early emergence of Eomes+ CD8 single-positive (CD8SP) thymocytes—cells predisposed to differentiate into VM T cells—and peripheral VM T cells. Notably, their development was significantly impaired in MHC-deficient neonates when Lin28b expression was inhibited in DN thymic progenitors. This highlights the critical role of Lin28b in MHC-independent VM T cell development. Our findings uncover an unconventional, MHC-independent pathway for VM T cell development, closely associated with unique hematopoiesis in early life. Funding Sources Supported by R21AI140106; R21AI138180 Topic Categories Hematopoiesis and Immune System Development (HEM)