Feedback regulation of T cell development: Manifestations in aging

Recent findings have indicated that mature T cells may regulate thymocytopoiesis in an age-related differential manner. The studies were based on T lymphocyte development in mouse fetal thymus stroma colonized with immature thymocytes and CD4⁺ T cells from young or old donors. In the present study, we used mathematical modeling and computer simulations in order to identify the thymocyte subsets that are the targets for this type of regulation, and the processes affected by it. Our results suggest that thymocyte development is subject to regulation through 2 feedback loops: mature CD4⁺ cells exert a negative feedback on the double-negative to double-positive transition and on double-positive subset growth, and a positive feedback on the double-positive to CD4 single-positive transition. These effects may operate, in young mice, through a reduction in the rate of death of CD4⁺8^- thymocytes, and a faster maturation of double-positive cells. In old mice, our simulations suggest that there may additionally be a reduction in double-positive proliferation rate. In some, but not all, of the simulations of old donor-derived thymocytes, we also had to assume a reduction in double-negative to double-positive differentiation, an increase in double-positive death rates, an increase of CD4⁺8^- cell division rate, and a decrease of differentiation to the CD8 lineage.