• Rinkee Kumari, Sushmita Chakraborty, Rashi Jain, Saswata Mitra, Anant Mohan, Randeep Guleria, Shivam Pandey, Uddeep Chaudhury, and Dipendra Kumar Mitra.
• Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India.
• Chest. 2021 Sep 1; 160 (3): 969-982.

BackgroundPulmonary 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 QuestionDoes the OX40 pathway influence the suppressive functions of Treg cells in PS?Study Design And MethodsFifty 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.ResultsWe 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.InterpretationWe 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.Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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