Regulatory T Cell Heterogeneity and Mechanisms of Lung Repair Following Acute Lung Injury

Recovery from acute respiratory distress syndrome (ARDS) and severe pneumonia depends on coordinated immune mechanisms that restore lung structure and function. However, the cellular and molecular programs driving this repair remain incompletely defined. Regulatory T cells (Tregs) are central mediators of inflammation resolution and tissue repair in experimental acute lung injury (ALI), and higher Treg frequencies among CD4+ T cells correlate with shorter mechanical ventilation in ARDS patients. Building on our prior work identifying conserved noncoding sequence 1 (CNS1)–dependent peripherally derived Tregs (pTregs) as essential for recovery from influenza-induced ALI, this proposal addresses three critical gaps: (1) how sex-specific TGFβ/CNS1 signaling governs the generation and function of reparative pTregs, (2) how the transcription factor Helios (Ikzf2) directs context-dependent epigenetic and tissue-residency programs that stabilize reparative Tregs, and (3) how Treg-derived matrix metalloproteinase 12 (Mmp12) orchestrates fibrin and thrombus resolution to restore alveolar integrity. We hypothesize that optimal lung repair requires a dynamically reprogrammed Treg state shaped by sex-dependent CNS1 induction, Helios-mediated adaptation, and Mmp12-driven proteolytic remodeling. To test this, we will integrate mechanistic studies in genetically engineered mouse models with translational analyses of biospecimens from patients with ARDS and acute pulmonary emboli. This work will define novel, targetable Treg pathways that promote lung repair and inform immunomodulatory therapies for ARDS and related thromboinflammatory lung diseases.