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bioRxiv · 10.64898/2026.05.01.722312

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

Hossain, M. S.·Mobeen, A.·Xiong, H.·Trevail, R.·Chen, L.·Suo, L.·Karimi, M.
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Abstract

Pulmonary hemorrhage (PH) is a life-threatening manifestation of systemic autoimmunity caused by immune-mediated disruption of the alveolar capillary barrier. Despite high mortality, the molecular checkpoints that shift destructive inflammation toward protective immune regulation remain poorly defined. Here, using the pristane-induced PH model, we identify interleukin-2-inducible T cell kinase (ITK) as a critical regulator of autoimmune lung injury. ITK deficiency (ITK-/- ) conferred near-complete protection from PH and associated multiorgan injury, accompanied by reduced proinflammatory monocytes and neutrophils and increased Foxp3 regulatory T cells (Tregs). Adoptive transfer of ITK-/-; Tregs protected wild-type recipients from PH and suppressed systemic proinflammatory cytokines, identifying Tregs as key mediators of tissue protection. Mechanistically, lung ITK-/- ; Tregs exhibited increased amphiregulin, a mediator of tissue repair. Transcriptomic profiling further showed that ITK loss reprogrammed Tregs toward a metabolically and functionally enhanced state, with enrichment of oxidative phosphorylation, mTORC1 and STAT5 signaling, and tissue-repair programs. These findings establish ITK as a regulator of the balance between pulmonary injury and reparative immunity and support targeting the ITK axis in severe inflammatory lung disease.

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Hossain, M. S., Mobeen, A., Xiong, H., Trevail, R., Chen, L., Suo, L., Karimi, M.. 2026-05-06. ITK Deficiency Attenuates Alveolar Hemorrhage by Enhancing Regulatory T Cell-Mediated Tissue Resilience. https://doi.org/10.64898/2026.05.01.722312

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