CNS1-dependent regulatory T cells shape recovery from acute lung injury.

Regulatory T cells (Tregs) play a crucial role in mediating recovery from acute lung injury (ALI). However, the complex roles of functionally heterogeneous Treg subsets in the lung during the resolution of acute inflammation remain unclear. To investigate the role of peripherally induced Tregs, we utilized mice lacking conserved noncoding sequence 1 (CNS1) of the Foxp3 locus, a genetic deletion that impairs peripheral Treg induction. We found that CNS1-deficient mice exhibit greater mortality and delayed resolution during ALI. Tregs induced via CNS1 modulated antiviral and proinflammatory immune responses in the lung during influenza. Mechanistically, single-cell RNA sequencing reveals that CNS1-deficient Tregs fail to fully engage the Treg transcriptional program that supports optimal suppressive and reparative function in the lung. Our findings highlight a critical role for CNS1-dependent peripherally induced Tregs in determining ALI severity, providing insight into how distinct Treg subpopulations may be therapeutically harnessed to mitigate tissue damage during respiratory disease.