Elucidating mechanisms regulating treg tissue responses driven by IL-33 in the lung

The National Heart, Lung, and Blood Institute awarded the University of Pittsburgh $100,228 on September 30, 2026, for research into mechanisms regulating regulatory T cell (Treg) tissue responses driven by IL-33 in the lung under the Cardiovascular Diseases Research program (CFDA 93.837).

The research addresses acute lung injury and acute respiratory distress syndrome by investigating how IL-33 stimulation enhances Treg reparative capacity. The investigator's preliminary data demonstrate that IL-33-stimulated Tregs protect against acute lung injury–induced mortality and promote alveolar macrophage restoration when delivered post-injury, whereas IL-2–stimulated Tregs suppress macrophage frequency. The project tests the hypothesis that limiting Treg expression of the IL-33 antagonist soluble ST2 while augmenting ST2 receptor expression will enhance Treg reparative responses and improve the effectiveness of Treg cell therapy for acute lung injury.

The award obligates $100,228 with a period of performance from September 30, 2026, through April 30, 2028. Work is performed in Pittsburgh, Pennsylvania. This is a Project Grant assistance type awarded to University of Pittsburgh as the recipient.

Abstract

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ards), are life-threatening conditions that result from direct or indirect lung damage, leading to uncontrolled inflammation, alveolar injury, and impaired oxygen exchange and impaired lung repair. Despite advancements in clinical care, including lung- protective ventilation and corticosteroids, ards remains a major cause of morbidity and mortality, with no targeted pharmacological treatments available. Resolution and restoration of lung function require clearing pro- debris and inflammatory cells while repairing the alveolar-capillary membrane. Effective therapies should both suppress inflammation and promote lung repair to prevent ards progression and reduce long-term sequalae. Regulatory t cells (tregs) are critical in maintaining homeostasis by suppressing other immune cells. Recently tregs have emerged as reparative cells when stimulated by IL-33 via the IL-33 receptor, ST2. Unfortunately, lung injury leading to ards seems to overwhelm endogenous treg responses and the lengthy manufacturing process of expanding autologous tregs limits their applicability as an effective therapy for acute lung injuries. My preliminary data demonstrate that IL-33 stimulates expression of ST2, while IL-2 alone promoted secretion of the IL-33 antagonist soluble ST2 (SST2). Both allogenic and syngeneic IL-33-stimulated treg were protective against ALI induced mortality when delivered 24 hours post lung injury and promoted the restoration of alveolar macrophages in the lung interstitium. This was in contrast to the suppressive IL-2 simulated treg group that limited alveolar macrophage frequency. Therefore, my hypothesis is that limiting treg SST2 expression, while augmenting expression of ST2 will enhance treg reparative responses and improve the effectiveness of treg cell therapy for ALI. I will directly test this hypothesis by addressing the following specific aims: 1. Define how treg regulate expression of ST2 isoforms. 2. Determine the capacity of IL-33-programmed syngeneic (SYN) or allogeneic (allo) treg adoptive cell therapy (act) to promote tissue repair and resolution after ALI. Completion of these aims will establish how treg regulate ST2/SST2 expression to balance repair and suppression. I will also determine whether IL-33 stimulated tregs or tregs engineered to have sustained ST2 expression in the absence of SST2 are effective against ALI mortality. These studies will also determine if allogenic treg are as effective as autologously sourced cells and address mechanisms by which treg modulate alveolar macrophage RE-establishment in the lung. Contribution to training: this proposal entails an extensive training plan to elucidate immunoregulatory and reparative functions of treg combined with superb mentorship in bioinformatics, immunology, and cell therapy. Together, the generated data will foster my professional development for conference talks and manuscript preparation. IT further integrates my interests in developing clinical therapies aimed at mitigating immune-mediated damage after ALI and provides strong foundations for an industry career by collaborating with renowned researchers in transplantation, regenerative medicine, and infectious disease.