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Inhibiting OX40 Restores Regulatory T-Cell Function and Suppresses Inflammation in Pulmonary Sarcoidosis

      Background

      Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous.

      Research Question

      Does the OX40 pathway influence the suppressive functions of Treg cells in PS?

      Study Design and Methods

      Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated.

      Results

      We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients’ BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4+Foxp3) and Treg (CD4+Foxp3+) cells obtained from the BALF of patients with PS. However, OX40 exerted contrasting impact on these T-cell subsets, enhancing effector T-cell functions (interferon γ, tumor necrosis factor α) while inhibiting Treg cell function (IL-10, transforming growth factor β). OX40 silencing or blocking on Treg cells resulted in restoration of their impaired functions.

      Interpretation

      We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS.

      Key Words

      Abbreviations:

      BALF (BAL fluid), IFN-γ (interferon γ), JNK (c-Jun N-terminal kinase), MAPK (mitogen-activated protein kinase), mRNA (messenger RNA), mTOR (mammalian target of rapamycin), NFAT (nuclear factor of activated T cell), NFκB (nuclear factor κ B), PB (peripheral blood), PBMC (peripheral blood mononuclear cell), PS (pulmonary sarcoidosis), siRNA (small interfering RNA), Teff (effector T), TGF-β (transforming growth factor β), Th (T helper), TNF-α (tumor necrosis factor α), Treg (regulatory T)
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