Expansion and maintenance of long lived effector CD8 T cells is modulated by inflammation

Abstract

Abstract Long-lived effector T cells (LLEC) are a circulating population of KLRG1 and CX3CR1 expressing memory CD8 T cells. LLEC were first described by the Hamilton Lab and are highly effective at clearing systemic infections compared to other memory T cells. However, LLEC express lower levels of IL-7 and IL-15 receptor chains and are poorly proliferative in specific pathogen free (SPF) mice as compared to central and effector memory T cells, which leads to a slow attrition of their numbers. The factors supporting LLEC expansion and persistence are unknown, and the goal of this study is to understand what internal and external factors contribute to LLEC expansion and maintenance. Data from models of chronic inflammation suggest pro-inflammatory factors contribute to the expansion and/or survival of LLEC. Specifically, we have found that LLEC populations are increased in young mice that have been exposed to a diverse mixture of microbes through co-housing with pet-shop mice. This co-housing model chronically increases systemic inflammation, and LLEC specific for model antigens not only expand more, but also persist longer than in SPF mice. Similarly, we also find increased LLEC in aged mice, another model associated with chronic inflammation. In preliminary work, we find that LLEC division is increased during cohousing, and that IL-18R expression is elevated, further suggesting that inflammatory cytokines not typically associated with T cell persistence may support LLEC proliferation. Ongoing studies will determine which specific inflammatory markers support LLEC expansion and maintenance, whether these factors are detrimental to other memory subsets, and if this process can be altered to improve T cell responses to infection and vaccination. Supported by grants from NIH (R01 AI143828).