Regulatory T Cell Induction and Retention in the Lungs Drives Suppression of Detrimental Type 2 Th Cells During Pulmonary Cryptococcal Infection

Lethal disease caused by the fungus, Cryptococcus neoformans, is a consequence of the combined failure to control pulmonary fungal replication and immunopathology caused by induced type-2 helper T (Th2) cell responses in animal models. In order to gain incites into immune regulatory networks, we examined the role of regulatory T (Treg) cells in suppression of Th2 cells, using a mouse model of experimental cryptococcosis. Upon pulmonary infection with Cryptococcus, Treg cells accumulated in the lung parenchyma independently of priming in the draining lymph node. Using peptide-MHCII molecules to identify Cryptococcus-specific Treg cells combined with genetic fate-mapping, we noted that a majority of the Treg cells found in the lungs were induced during the infection. Additionally, we found that Treg cells utilized the transcription factor, Interferon Regulatory Factor 4 (IRF4), to dampen harmful Th2 cell responses, as well as mediate chemokine retention of Treg cells in the lungs. Taken together, induction and IRF4-dependent localization of Treg cells in the lungs allow Treg cells to suppress the deleterious effects of Th2 cells during cryptococcal infection