The Lifespan of Naïve CD4 T cells is a Critical Determinant for the Cellular Aging in Periphery (46.2)

Abstract

Abstract Cell intrinsic functional defect in aged naive CD4 T cells is a key cause of an age-associated increase in susceptibility to infectious diseases. However the causes of the CD4 T cell defects and how they develop are largely unknown. We have suggested that many defects develop during the sojourn of the naïve CD4 T cells in the periphery. We report here that aged naïve CD4 T cells have a longer lifespan than young cells even when transferred to young intact hosts. In vitro studies suggest that their increased longevity is regulated by an intrinsic property for survival. Consistent with this, aged naïve CD4 T cells express reduced level of a pro-apoptotic molecule, Bim, and the reduction of Bim in naïve CD4 T cells is sufficient for longer lifespan in vivo. This longer lifespan of aged naïve T cells could contribute to the maintenance of T cell homeostasis in aged mice. On the other hand, shutdown of new T cell emigration from the thymus by thymectomy leads to long-term persistence of remaining naïve T cells in the periphery and accelerates development both of the functional defects and of increased lifespan in naive CD4 T cells. Neither of these is observed when new naïve T cells are derived from aged hematopoietic stem cells. Thus, these results suggest that development of functional defects in aged naive CD4 T cells is associated with long-term persistence of aged naïve T cells due to their increased lifespan in periphery. The authors have no financial conflict of interest. This work was supported by National Institutes of Health Grants AG025805, AG021600 and the Trudeau Institute.