ITK Deficiency Attenuates Alveolar Hemorrhage by Enhancing Regulatory T Cell-Mediated Tissue Resilience

Pulmonary hemorrhage (PH) is a life-threatening manifestation of systemic autoimmunity characterized by immune-mediated disruption of the alveolar-capillary barrier. Despite mortality rates exceeding 50%, the molecular checkpoints that govern the transition from destructive inflammation to protective immune regulation remain poorly defined. Building on our discovery that interleukin-2-inducible T cell kinase (ITK) uncouples pathogenic inflammation from protective immunity, we investigated ITK as a central regulator of autoimmune lung injury. Using the pristane-induced PH model, we show that ITK deficiency confers near-complete protection against PH and associated multi-organ injury. This protection is accompanied by marked remodeling of the T cell compartment, including expansion of CD44⁺CD122⁺Eomes⁺T-bet⁺ memory-like subsets and significant enrichment of Foxp3⁺ regulatory T cells (Tregs). Notably, adoptive transfer of ITK-deficient Tregs was sufficient to rescue PH and suppress systemic proinflammatory cytokine production in wild-type recipients, identifying these cells as key mediators of tissue protection. Transcriptomic profiling further revealed that loss of ITK signaling reprograms Tregs toward a metabolically and functionally enhanced state, with enrichment of oxidative phosphorylation (OXPHOS), mTORC1, STAT5 signaling, and tissue-repair-associated programs. Together, these findings identify ITK as a critical regulator of the balance between pulmonary injury and reparative immunity and provide a mechanistic rationale for targeting the ITK axis in severe inflammatory lung disease. Highlights ITK deficiency protects against pristane-induced pulmonary hemorrhage (PH) Loss of ITK expands "super-fit" canonical and non-canonical Tregs ITK-deficient Tregs exhibit enriched mTORC1, OXPHOS, and IL-10 production Transfer of ITK-deficient Tregs rescues established PH and reverses proteinuria ITK uncouples pathogenic inflammation from reparative tissue immunity