Collagen V reactive exTregulatory cells in chronic hypoxia-induced pulmonary hypertension

Group 3 pulmonary hypertension (PH) is defined by the World Health Organization as PH that results from hypoxia and/or lung diseases, including chronic obstructive pulmonary disease (COPD), sleep apnea, and high-altitude exposure. We have previously demonstrated the important contributions of the inflammatory response seen in chronic hypoxia (CH)-induced PH. We reported that CH (380 mmHg) decreased the suppressive capacity of anti-inflammatory T regulatory cells (Tregs) and increased T helper 17 (TH17) cells in the mouse spleen. Additionally, in the same model, we identified a subset of CD4+ T cells of the Treg lineage, termed exTregs, that expressed TH17 markers. Finally, we found that collagen type V (Col V), a protein known to elicit antigenic self-responses, is upregulated in the lungs following CH exposure. Whether the shift in immune cells and the upregulation of Col V are associated was unknown. Therefore, we hypothesized that CH-exposed mice would harbor more Col V-reactive exTregs. We developed a major histocompatibility type II (MHC-II) tetramer loaded with a Col V peptide (NIH Tetramer Core), and using flow cytometry, we found the number of Col V-reactive exTregs to be increased following 5 days of CH, coinciding with maximum proliferation of cells in the pulmonary arterial wall, a hallmark of PH. However, following 21 days of CH, at a time when PH is established but proliferation is undetectable, we observed an increase in Col V-reactive Tregs but not exTregs within the spleen. In conclusion, these results suggest that Col V-exTregs contribute to the onset of CH-induced PH. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.