Therapeutic manipulation of memory T cell homeostasis in vivo

Abstract

Abstract After a primary immune response, a cohort of antigen-specific memory T cells are retained in vivo conferring long term protection against that specific pathogen. Over a lifetime, the accumulation of a memory T cell repertoire with specificities to multiple pathogens, collectively keeps the host safe against prevalent environmental threats. Other than booster vaccinations which narrowly increase the frequency of a single antigen-specific cohort, there are no viable strategies available to globally alter the total memory T cell population in vivo. Since memory T cells are thought be maintained by trophic signals from cytokines or self-MHC- both of which are available from endogenous antigen-presenting cells (APC)- we hypothesized that enhancing APC numbers in vivo can be a viable strategy to amplify memory T cells. Towards this end we treated mice with FMS-like tyrosine kinase 3 ligand (Flt3l) or specific self-peptides known to increase the peripheral survival of cohorts of CD4 T cells. After an acute expansion of dendritic cells (DCs) following Flt3l treatment, we observed an increase in effector memory CD4s and CD8s, but not in naïve T cells. Over the short term, this increase was independent of alterations in the thymus. On cessation of Flt3l treatment, the increase in DCs was not sustained, and the population of memory T cells also returned to steady state, suggesting restoration of competitive homeostasis. In contrast to this global effect, administering an endogenous self-peptide used by a small subset of peripheral T cells did not significantly alter the overall number or distribution of the memory repertoire. Taken together, these data suggest new options to manipulate memory T cell populations in clinically relevant situations.