The altered T cell landscape in Systemic Sclerosis patients is characterized by dysfunctional type 1 immunity
Year: 2025
Type: preprint
Study design: Observational Study
Abstract: Background T cells in patients with chronic autoimmunity show features of dysfunction and exhaustion. However, the functionally-defined T cell subsets affected by these changes remain poorly characterized. Here, we sought to reveal aberrations in the composition, phenotype and function of canonical T cell subsets in the blood of Systemic Sclerosis (SSc) patients, compared to healthy subjects and Systemic Lupus Erythematosus (SLE) patients. Methods We developed a novel multidimensional flow-cytometry panel to simultaneously detect lineage-defining transcription factors, co-inhibitory receptors and other functional markers to characterize T cell subsets without in vitro restimulation. We compared T cell landscapes in SSc and SLE patients, and healthy subjects, using Optimized t-SNE and PhenoGraph algorithms. Cytokine production in patient samples was determined using intracellular cytokine staining. Transcriptomic analysis was performed to assess the role of IFN-γ in fibroblasts. Results The data show altered distribution and aberrant functional states of transcription factor-defined T cell subsets in patients with autoimmunity, with shared and unique features between diseases and their subtypes. Strikingly, SSc and SLE patients showed a severe deficiency in subsets of CD8 + and CD4 - CD8 - T cells that expressed T-bet, which is critical for IFN-γ-dependent type 1 immunity, and exhibited features of exhaustion. Moreover, TIGIT + Foxp3 + regulatory T cells, known to suppress Th1 responses, were selectively increased in SSc. Functionally, T cells from SSc patients produced less IFN-γ, a cytokine that suppresses pro-fibrotic gene expression in fibroblasts. Conclusion Our study demonstrates that SSc patients have a defective IFN-γ-producing T cell compartment that may lead to reduced anti-fibrotic T cell activity, enabling chronic fibrosis development. Funding National Institute of Allergy and Infectious Diseases/NIH, National Institute of Arthritis and Musculoskeletal Diseases/NIH, National Heart, Lung and Blood Institute/NIH, National Scleroderma Foundation, National Jewish Health
Authors: Victoria Volfson-Sedletsky, Hannah A. DeBerg, Mitch L. Fahning, Ian R. Rifkin, Andreea M. Bujor, Daniel J. Campbell, Peter A. Morawski, Anna C. Belkina, Hans Dooms
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Scleroderma Foundation
OpenAlex ID: W7115073726