Abstract
BackgroundT cell Ig and ITIM domain (TIGIT)/CD226 pathway has a critical role in regulating T cell responses and has come to the forefront in cancer as a promising immunotherapeutic target. However, its role in autoimmune diseases is just beginning to be elucidated. Dermatomyositis (DM) is an autoimmune disease, in which T cell dysregulation plays a pivotal role, and importantly, it is a common immune-related adverse event in response to treatment of cancers with immune checkpoint inhibitors, but no studies have implicated the TIGIT/CD226 axis in DM.MethodsWe recruited 30 treatment-naïve DM patients and 26 healthy controls. Flow cytometry analysis was used to investigate the co-expression of TIGIT and CD226 on T cells in blood samples. Magnetic bead or FACS-based cell isolation, T cell proliferation assay, and intracellular cytokine staining were performed to analyze the functions of different TIGIT/CD226 phenotypes. Recombinant proteins CD155, CD112, and anti-CD226 antibodies were used to suppress the function of TIGIT/CD226-expressing CD4 T cells.ResultsFour distinct subsets of T cells based on TIGIT/CD226 co-expression, TIGIT+CD226−, TIGIT+CD226+, TIGIT−CD226+, and TIGIT−CD226−, were identified and characterized in DM patients. Our data showed that the function of CD4 T cell subset varied by the TIGIT/CD226 phenotype. An elevated TIGIT+CD226+ CD4 subset with enhanced effector function was observed in patients with DM, especially the patients complicated with interstitial lung disease. This subpopulation was closely related to DM activity and decreased significantly in DM remission after treatment. Furthermore, the effector function of TIGIT+CD226+ CD4 subset could be suppressed by blocking CD226.ConclusionOur data revealed that the TIGIT and CD226 expression profiles could be used to identify functionally distinct subsets of CD4 T cells and TIGIT+CD226+ CD4 T cells is a significant subset in DM with enhanced frequency and effector function. This abnormal subset could be suppressed by blocking CD226, providing insight into the therapeutic target of the TIGIT/CD226 axis.
Highlights
T cell Ig and ITIM domain (TIGIT)/CD226 pathway has a critical role in regulating T cell responses and has come to the forefront in cancer as a promising immunotherapeutic target
(See figure on previous page.) Fig. 3 Effector function of TIGIT+CD226+ CD4 T cells was altered in patients with DM. a The functional comparisons between DM and healthy controls showed that expression of HLA-DR, the percentage of proliferating cells, and tumor necrosis factor α (TNF-α) production potential of TIGIT+CD226+ subset in DM were significantly higher than that of healthy controls. b In DM patients with interstitial lung disease (ILD), the expression of HLA-DR, the percentage of proliferating cells, and cytokine production potential of TIGIT+CD226+ CD4 T cells were increased compared to in DM patients without ILD. c Representative fluorescent-activated cell sorting (FACS) plots of different groups
We show for the first time that TIGIT and CD226 expression profiles can be used to identify functionally distinct subsets of CD4 T cells
Summary
T cell Ig and ITIM domain (TIGIT)/CD226 pathway has a critical role in regulating T cell responses and has come to the forefront in cancer as a promising immunotherapeutic target. Dermatomyositis (DM) is an autoimmune disease, in which T cell dysregulation plays a pivotal role, and importantly, it is a common immune-related adverse event in response to treatment of cancers with immune checkpoint inhibitors, but no studies have implicated the TIGIT/CD226 axis in DM. An increasing number of studies have suggested that DM develops as an immune-related adverse event in response to treatment of cancers with immune checkpoint inhibitors (e.g., CTLA-4 inhibitor, ipilimumab) [5]. These results suggest that an altered balance between co-stimulatory and coinhibitory molecules on T cells contributes to DM pathogenesis
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