Impact of Chronic Infection-Induced Inflammation on TREG Cell Homeostasis

Thymically-derived regulatory T (Treg) cells express the transcription factor Foxp3 and are maintained at homeostasis by the cytokine IL-2. These specialized cells mediate peripheral tolerance and determine the balance between protective and pathological T cell responses during infection. Acute infection of mice with Toxoplasma gondii results in thymic atrophy and reduced production of IL-2 that correlate with a "crash" in Treg cell populations. Here, kinetic studies of mice infected with T. gondii reveal that as acute infection resolves, there is a restoration of IL-2 and reversal of thymic hypertrophy associated with partial restoration of the Treg compartment. Fate-mapping of the Treg cell compartment showed that infection-induced thymic involution did not severely impact the ability to generate Treg cells. Moreover, the peripheral Treg cells that survived the infection-induced "crash" were the major contributors to the rebuilt Treg compartment. However, the use of antiparasitic drugs to reduce chronic parasite replication and inflammation improved generation of thymic Treg cells that contributed to the rebuilding of the Treg cell pool. These studies illustrate that infection-induced loss of IL-2 and Treg cells is transient, and despite the ability to generate thymically derived Treg cells, those peripheral Treg cells that survive the acute "crash" are preferentially maintained.