T-bet Expression in Peripheral Th17.0 Cells Is Associated With Pulmonary Function Changes in Sarcoidosis.

Abstract

Background: Interferon-gamma (IFN-γ) is a key mediator of sarcoidosis-related granulomatous inflammation. Previous findings of IFN-γ-producing Th17 cells in bronchoalveolar lavage fluid from sarcoidosis patients invokes the transition of Th17.0 cells to Th17.1 cells in the disease's pathogenesis. Since the T-bet transcription factor is crucial for this transition, the goal of this study was to determine if T-bet expression in Th17.0 cells reflects the extent of granulomatous inflammation in sarcoidosis patients as assessed by clinical outcomes. Methods: Using a case-control study design, we identified two groups of sarcoidosis subjects (total N = 43) with pulmonary function tests (PFTs) that either (1) changed (increased or decreased) longitudinally or (2) were stable. We used flow cytometry to measure the transcription factors T-bet and RORγt in Th1, Th17.0, and Th17.1 cell subsets defined by CCR6, CCR4 and CXCR3 in blood samples. We compared the percentages of T-bet+ cells in RORγt+Th17.0 cells (defined as CCR6+CCR4+CXCR3-) based on subjects' PFT group. We also assessed the relationship between the direction of change in PFTs with the changes in %T-bet+ frequencies using mixed effects modeling. Results: We found that T-bet expression in subjects' RORγt+Th17.0 cells varied based on clinical outcome. The T-bet+ percentage of RORγt+Th17.0 cells was higher in the cases (subject group with PFT changes) as compared to controls (stable group) (27 vs. 16%, p = 0.0040). In comparisons before and after subjects' PFT changes, the T-bet+ frequency of RORγt+Th17.0 cells increased or decreased in the opposite direction of the PFT change. The percentage of these T-bet+ cells was also higher in those with greater numbers of involved organs. Serum levels of interferon-γ-induced chemokines, CXCL9, CXCL10, and CXCL11, and whole blood gene expression of IFN-γ-related genes including GBP1, TAP1, and JAK2 were independently positively associated with the T-bet+ frequencies of RORγt+Th17.0 cells. Conclusions: These data suggest that expression of T-bet in Th17.0 cells could reflect the extent of granulomatous inflammation in sarcoidosis patients because they represent a transition state leading to the Th17.1 cell phenotype. These findings indicate that Th17 plasticity may be part of the disease paradigm.

• Authors: Nicholas K Arger, Siddharth Machiraju, Isabel E Allen, Prescott G Woodruff, Laura L Koth
• Journal: Frontiers in immunology (Front Immunol) Vol. 11 Pg. 1129 ( 2020) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 32774332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2020 Arger, Machiraju, Allen, Woodruff and Koth.

Chemical References

• Biomarkers
• Nuclear Receptor Subfamily 1, Group F, Member 3
• RORC protein, human
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Interferon-gamma

Topics

• Adult
• Aged
• Biomarkers (blood, metabolism)
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Case-Control Studies
• Female
• Humans
• Interferon-gamma (metabolism)
• Lung (immunology, metabolism, physiopathology)
• Male
• Middle Aged
• Nuclear Receptor Subfamily 1, Group F, Member 3 (metabolism)
• Prognosis
• Sarcoidosis, Pulmonary (immunology, metabolism, physiopathology)
• T-Box Domain Proteins (metabolism)
• Th17 Cells (immunology, metabolism)