Impact of Toxoplasma gondii on Treg homeostasis

Project Summary/Abstract Acute infection of mice with Toxoplasma gondii results in a collapse of the regulatory T cell (Treg) population. While the infection-induced collapse of Treg cells has been defined, the re-building of the compartment and the long-term impact of the crash have not been studied. Tregs were originally believed to be a monolithic population of suppressor cells, but there is recognition of distinct subsets termed central and effector Tregs. At homeostasis, central Tregs (cTregs) are a relatively quiescent subset whereas effector Tregs (eTregs) exhibit hallmarks of recent TCR engagement and potent suppressive activity. The studies presented here reveal that infection results in a skewing of the composition of the Treg compartment after the collapse. My data shows as infection resolves, there is restoration of IL-2 production and thymic output and the Treg compartment returns to near normal levels, yet there remains a marked increase in the ratio of cTreg:eTreg cells. The use of lineage tracing shows that the post-crash Treg compartment is dominated by Treg cells that were present during collapse but a population of newly-generated Tregs emerge from the thymus These observations raise fundamental questions about the rebuilding process: (1) What cytokines contribute to re-population? (2) Does ongoing inflammation associated with chronic infection affect Treg output and phenotype? And (3) Does the Treg collapse lead to permanent alterations to the population structure or function of the Treg compartment? To get at these questions, I will utilize high-parameter flow cytometry, multi-omic sequencing and an in vivo Treg tracing model to investigate the Treg compartment throughout infection with T.gondii. I will interrogate the impact of IL-2 and IL-7 on Treg re-population and determine how infection shapes the re-built Treg compartment. These studies will enhance our understanding of Treg biology during infection and identify possible approaches for manipulating Treg subsets therapeutically.