CNS1-induced Peripheral Regulatory T cells in the Resolution of Acute Lung Injury 2115

Abstract Description RATIONALE Regulatory T cells (Tregs) perform essential functions during the resolution of acute lung injury. Tregs regulate immune cell trafficking into the lung, suppress excessive immune responses in late injury, and contribute to tissue repair processes following injury. However, the role of thymically-derived Tregs (tTregs) and peripherally-induced Tregs (pTregs) in these processes remain unknown. A conserved noncoding sequence in the Foxp3 promoter, CNS1, is an important inducer of Foxp3 expression in CD4+ T cells to generate pTregs. RESULTS Using a mouse model that lacks peripheral induction of Foxp3 expression (Foxp3ΔCNS1-gfp ΔCNS1 mice, gift from A. Rudensky), we show that induction of Foxp3 expression in CD4+ T cells via CNS1 has a role in survival from acute lung injury. We also find that Tregs in the lungs of ΔCNS1 mice display aberrant phenotypes, namely the failure to develop Tregs with reactivity to a common mouse-adapted H1N1 (PR8) antigen. Finally, we report several cell-intrinsic phenotypes of ΔCNS1 Tregs in a mixed chimeric environment, including elevated Foxp3, Helios, CD25, and CD103 expression, and decreased CD44 expression. CONCLUSIONS AND FUTURE DIRECTIONS: Our results suggest that induction of Foxp3 expression in CD4+ T cells via CNS1 is important in acute lung injury resolution. Future directions will elucidate how CNS1 affects Treg transcriptional profiles and identify potential T cell receptor repertoire differences in these Treg cell subsets. Funding Sources The National Heart, Lung, and Blood Institute of the National Institutes of Health supported research: R01HL152077. Morgan McCullough is supported through The American Association of Immunologists Careers in Immunology Fellowship Program. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)