Expression and function of co-inhibitory receptors PD-1, TIGIT, TIM-3, and LAG-3 in systemic sclerosis
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Systemic sclerosis is an autoimmune connective tissue disorder associated with fibrosis of the skin and internal organs. Co-inhibitory receptors (Co-IRs) regulate immune responses and have been shown to control autoimmune phenotypes. We explored the role of these receptors in systemic sclerosis through their expression in circulating lymphocytes and their control of lymphocyte function in vitro and in vivo. We found that individual co-IRs were increased on specific lymphocyte populations in patients. PD-1 was increased on CD4+ memory T cells, while TIGIT was increased on both CD4+ and CD8+ memory T cells. Changes in TIM-3 expression were limited to cytotoxic NK cell populations while LAG-3 remained low and unchanged on all lymphocyte populations identified. The blockade of PD-1 in vitro, in particular, had a greater effect on modulating cytokine production in systemic sclerosis PBMCs compared to the blockade of TIGIT and TIM-3 versus a similar modulation of cytokine production by PD-1, TIGIT, and TIM-3 in healthy controls. This indicates an increased level of exhaustion in PBMCs from systemic sclerosis patients that can be overcome by the blockade of PD-1, but not TIGIT or TIM-3. However, the blockade of TIM-3 in vitro had the greatest effect on modulating the production of soluble factors that regulate pro-fibrotic changes in gene expression in systemic sclerosis fibroblasts. In vivo, TIGIT and TIM-3 were unable to consistently regulate the autoimmune phenotype of sclerodermatous GvHD mice. These data indicate a potential function for lymphocyte exhaustion in regulating the autoimmune and inflammatory response in systemic sclerosis, with specific co-IRs playing defined roles in disease pathogenesis.