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.