Year: 2021
Type: conference-abstract
Abstract: RATIONALE: FoxP3 regulatory T cells (Tregs) participate in maintaining immunological tolerance.Tregs that simultaneously express the transcription factors, FoxP3 and T-bet, possess functional characteristics that allow for enhanced suppression of Th1 responses in mouse models.T-bet induces expression of the CXCR3 chemokine receptor that allows homing into tissues.Because the central cytokine of sarcoidosis inflammation is interferon-gamma, we hypothesized that there would be an association between the proportion of circulating Foxp3+ Treg cells that express these molecules (T-bet and CXCR3) and clinical outcomes in sarcoidosis patients.METHODS: Healthy volunteers and two independent cohorts of sarcoidosis patients meeting ATS criteria for diagnosis underwent sample collection and processing of cells for flow cytometry using the following gating strategy: singlets, live cells, CD3+, CD4+, CD45RA, CD45RO, CD127lo, FoxP3+, T-bet+, and CXCR3+.Proportions of T-bet-expressing Tregs were compared between healthy and sarcoidosis patients and between patients with different clinical courses.Progression of sarcoidosis was defined as a greater than 10% drop in spirometry values or a greater than 15% drop in diffusing capacity.RESULTS: In the cohort that had longitudinal blood sampling, we found that the proportion of circulating Tregs expressing T-bet and CXCR3 were lower in the 44 patients with a diagnosis of pulmonary sarcoidosis compared to 17 healthy volunteers (P=0.028).Within these sarcoidosis patients, we found that the proportion of these cells were maintained at higher levels over two time-points in patients who had clinical deterioration (defined by a lung function drop over the 36-month follow up time) compared to those who had a stable course (p<0.0001).To determine the proportions of these T-bet FoxP3 Tregs in the lung, we analyzed the bronchoalveolar lavage (BALF) samples from a second independent cohort that underwent bronchoscopy with lavage.We found that the proportion of Tbet-expressing FoxP3 cells in BALF were higher in 6 patients who had progression of their sarcoidosis compared to 7 patients who had remitted sarcoidosis (p=0.035).CONCLUSION: Using two independent cohorts of patients, we found that the proportion of T-bet expressing FoxP3 Tregs were higher in the blood and BAL in patients who had clinical deterioration.Since experimental evidence from mouse models indicate that these Tbet expressing Tregs promote suppression of Th1 responses, more studies are needed to understand if the functional properties of these cells are defective in suppressing Th1 responses in patients with progression of sarcoidosis.
Authors: P. Grewal, N. Arger, N.Y. Hamzeh, L. Koth, B. O'Connor
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4247303265