The altered T cell landscape in Systemic Sclerosis patients is characterized by dysfunctional type 1 immunity.

Volfson-Sedletski, V.; DeBerg, H. A.; Fahning, M. L.; Rifkin, I. R.; Bujor, A. M.; Campbell, D. J.; Morawski, P. A.; Belkina, A. C.; Dooms, H.

doi:10.64898/2025.12.10.693457

bioRxiv · 10.64898/2025.12.10.693457

The altered T cell landscape in Systemic Sclerosis patients is characterized by dysfunctional type 1 immunity.

Volfson-Sedletski, V.·DeBerg, H. A.·Fahning, M. L.·Rifkin, I. R.·Bujor, A. M.·Campbell, D. J.·Morawski, P. A.·Belkina, A. C.·Dooms, H.

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Abstract

BackgroundT 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. MethodsWe 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-{gamma} in fibroblasts. ResultsThe 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-{gamma}-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-{gamma}, a cytokine that suppresses pro-fibrotic gene expression in fibroblasts. ConclusionOur study demonstrates that SSc patients have a defective IFN-{gamma}-producing T cell compartment that may lead to reduced anti-fibrotic T cell activity, enabling chronic fibrosis development. FundingNational 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

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Volfson-Sedletski, V., DeBerg, H. A., Fahning, M. L., Rifkin, I. R., Bujor, A. M., Campbell, D. J., Morawski, P. A., Belkina, A. C., Dooms, H.. 2025-12-13. The altered T cell landscape in Systemic Sclerosis patients is characterized by dysfunctional type 1 immunity.. https://doi.org/10.64898/2025.12.10.693457

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