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

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.

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.

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.

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.

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.