T cell subsets in Systemic Sclerosis patients show features of exhaustion and reduced anti-fibrotic activities

Abstract

Abstract Systemic Sclerosis (SSc) or Scleroderma is a chronic autoimmune disease where immune cells contribute to the initiation and/or progression of microvascular damage and fibrosis, leading to devastating tissue malfunction often resulting in high morbidity and mortality. We recently discovered that PBMCs from SSc patients show increased expression of various co-inhibitory receptors, consistent with the presence of a state of chronic immune activation and dysfunction. Here, we sought to identify and functionally characterize dysregulated T cell subsets in SSc, and determine their role in pathogenic fibroblast activation. We used multi-parameter spectral flow cytometry and in vitro T cell/fibroblast co-culture assays to understand the role of T cell dysfunction and exhaustion in fibrosis, using clinical samples from a well-defined cohort of SSc patients. Our immunophenotyping analysis revealed that T cell populations in SSc patients show features of T cell exhaustion, such as enhanced expression of the co-inhibitory receptors PD-1 and TIGIT, and reduced production of the anti-fibrotic cytokine IFN-γ. PD-1+TIGIT+ T cells were found in peripheral blood as well as lung and skin of SSc patients. In addition, we found a significant reduction of immune cell subsets expressing the transcription factor T-bet in the blood of SSc patients, suggesting a reduced presence of immune cells that counteract a pro-fibrotic Type 2 immune response in SSc. In support of this, isolated T cell subsets from SSc patients showed reduced capacity to limit collagen production in T cell/fibroblast co-cultures. Together, our data suggest that T cells with anti-fibrotic activities are driven into a state of exhaustion in SSc, enabling the progression of fibrosis. Supported by grants from NIH (R21 AR071580) and the National Scleroderma Foundation (Walter & Marie Coyle Research Grant)