The altered T cell landscape in systemic sclerosis patients is characterized by dysfunctional type 1 immunity
Abstract
T cells in patients with chronic autoimmunity show features of dysfunction. However, the functionally defined T cell subsets that are 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 with healthy subjects and systemic lupus erythematosus (SLE) patients. Therefore, 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 opt-SNE (optimized t-distributed stochastic neighbor embedding) and PhenoGraph algorithms. 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 deficiencies in subsets of CD8+ and CD4−CD8− T cells that expressed T-bet, which is critical for IFN-γ–dependent type 1 immunity. Moreover, TIGIT+Foxp3+ regulatory T cells, which suppress T helper 1 responses, were increased in diffuse cutaneous SSc and SLE patients. Functionally, T cells from SSc patients produced less IFN-γ, a cytokine that suppresses profibrotic gene expression in fibroblasts, as we demonstrate by transcriptomic analysis. Our study supports a model in which IFN-γ opposes canonical fibrotic gene programs in fibroblasts, and deficiencies in the IFN-γ–producing T cell compartment in SSc patients therefore may contribute to chronic fibrosis development. Aberrant T cell subsets in SSc and SLE represent targets for corrective immunotherapy.
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BibTeX
@article{volfsonsedletsky2026altered,
title = {{The altered T cell landscape in systemic sclerosis patients is characterized by dysfunctional type 1 immunity}},
author = {Victoria Volfson-Sedletsky and Hannah A DeBerg and Mitch L Fahning and Ian R Rifkin and Andreea M Bujor and Daniel J Campbell and Peter A Morawski and Anna C Belkina and Hans Dooms},
journal = {The Journal of Immunology Author Choice},
year = {2026},
month = nov,
doi = {10.1093/jimmun/vkag288},
url = {https://doi.org/10.1093/jimmun/vkag288},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The altered T cell landscape in systemic sclerosis patients is characterized by dysfunctional type 1 immunity
AU - Victoria Volfson-Sedletsky
AU - Hannah A DeBerg
AU - Mitch L Fahning
AU - Ian R Rifkin
AU - Andreea M Bujor
AU - Daniel J Campbell
AU - Peter A Morawski
AU - Anna C Belkina
AU - Hans Dooms
PY - 2026
DA - 2026/11/04
JO - The Journal of Immunology Author Choice
DO - 10.1093/jimmun/vkag288
UR - https://doi.org/10.1093/jimmun/vkag288
AB - T cells in patients with chronic autoimmunity show features of dysfunction. However, the functionally defined T cell subsets that are 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 with healthy subjects and systemic lupus erythematosus (SLE) patients. Therefore, 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 opt-SNE (optimized t-distributed stochastic neighbor embedding) and PhenoGraph algorithms. 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 deficiencies in subsets of CD8+ and CD4−CD8− T cells that expressed T-bet, which is critical for IFN-γ–dependent type 1 immunity. Moreover, TIGIT+Foxp3+ regulatory T cells, which suppress T helper 1 responses, were increased in diffuse cutaneous SSc and SLE patients. Functionally, T cells from SSc patients produced less IFN-γ, a cytokine that suppresses profibrotic gene expression in fibroblasts, as we demonstrate by transcriptomic analysis. Our study supports a model in which IFN-γ opposes canonical fibrotic gene programs in fibroblasts, and deficiencies in the IFN-γ–producing T cell compartment in SSc patients therefore may contribute to chronic fibrosis development. Aberrant T cell subsets in SSc and SLE represent targets for corrective immunotherapy.
SN - 0022-1767
SN - 1550-6606
ER -