Inhibiting OX40 restores regulatory T cells function and suppresses inflammation in pulmonary sarcoidosis.

Abstract Background Pulmonary sarcoidosis (PS) is a non-caseating granulomatous disease with unknown etiology. 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, which is essential for T cell functions and memory development, but its impact on Treg cells is ambiguous. Research question Whether OX40 pathway influences the suppressive functions of Treg cells in PS? Study design and Methods: 50 treatment naive PS patients and 30 Healthy control subjects were recruited for this study. Polychromatic flowcytometry based immunological assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time PCR, siRNA and pharmacological inhibitors, the impact of OX40 on Tregs function was investigated. Results We observed enrichment of Th9 cells perhaps for the first time along with Th1, Th17 and Treg cells in Bronchoalveolar Lavage Fluid (BALF) compared to PB of patients. However, Treg cells were observed 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 BAL of PS patients. However, OX40 exerted contrasting impact on these T cell subsets; enhancing effector T cell functions (IFN-γ, TNF-α) while inhibiting Treg cell function (IL-10, TGF-β). OX40 silencing or blocking on Treg cells resulted in restoration of its impaired functions. Interpretation We propose that inhibiting OX40 pathway may constitute therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in PS patients.