Wenli Li1, Chuiwen Deng2, Hanbo Yang1, Xin Lu1, Shanshan Li1, Xia Liu1, Fang Chen1, Lida Chen3, Xiaoming Shu1, Lu Zhang1, Qingyan Liu1, Guochun Wang1, Qinglin Peng4. 1. Department of Rheumatology, China-Japan Friendship Hospital, Ying Hua East Road, Chao Yang District, Beijing, 100029, People's Republic of China. 2. Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. 3. Department of Blood Transfusion, China-Japan Friendship Hospital, Beijing, People's Republic of China. 4. Department of Rheumatology, China-Japan Friendship Hospital, Ying Hua East Road, Chao Yang District, Beijing, 100029, People's Republic of China. pqinglin@163.com.
Abstract
BACKGROUND: 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. 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. METHODS: We 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. RESULTS: Four 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. CONCLUSION: Our 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.
BACKGROUND: 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. 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. METHODS: We recruited 30 treatment-naïve DMpatients 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. RESULTS: Four 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 DMpatients. 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. CONCLUSION: Our 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.
Entities:
Keywords:
CD226; Co-inhibitory receptor; Co-stimulatory receptor; Dermatomyositis; T cell Ig and ITIM domain
Authors: Amit K Maiti; Xana Kim-Howard; Parvathi Viswanathan; Laura Guillén; Xiaoxia Qian; Adriana Rojas-Villarraga; Celi Sun; Carlos Cañas; Gabriel J Tobón; Koichi Matsuda; Nan Shen; Alejandra C Cherñavsky; Juan-Manuel Anaya; Swapan K Nath Journal: Rheumatology (Oxford) Date: 2010-03-24 Impact factor: 7.580
Authors: Andreas E R Fasth; Maryam Dastmalchi; Afsar Rahbar; Stina Salomonsson; Jayesh M Pandya; Eva Lindroos; Inger Nennesmo; Karl-Johan Malmberg; Cecilia Söderberg-Nauclér; Christina Trollmo; Ingrid E Lundberg; Vivianne Malmström Journal: J Immunol Date: 2009-09-14 Impact factor: 5.422
Authors: K Kurasawa; Y Nawata; K Takabayashi; K Kumano; Y Kita; Y Takiguchi; T Kuriyama; M Sueishi; Y Saito; I Iwamoto Journal: Clin Exp Immunol Date: 2002-09 Impact factor: 4.330
Authors: Xi Li; Rouzheng Wang; Peiwen Fan; Xuan Yao; Ling Qin; Yanchun Peng; Miaomiao Ma; Neil Asley; Xuimei Chang; Yaning Feng; Yunhui Hu; Yonghong Zhang; Chris Li; Gregory Fanning; Stephanie Jones; Clare Verrill; David Maldonado-Perez; Paul Sopp; Craig Waugh; Stephen Taylor; Simon Mcgowan; Vincenzo Cerundolo; Christopher Conlon; Andrew McMichael; Shichun Lu; Xiyan Wang; Ning Li; Tao Dong Journal: Front Oncol Date: 2019-10-25 Impact factor: 6.244
Authors: Ingrid E Lundberg; Anna Tjärnlund; Matteo Bottai; Victoria P Werth; Clarissa Pilkington; Marianne de Visser; Lars Alfredsson; Anthony A Amato; Richard J Barohn; Matthew H Liang; Jasvinder A Singh; Rohit Aggarwal; Snjolaug Arnardottir; Hector Chinoy; Robert G Cooper; Katalin Dankó; Mazen M Dimachkie; Brian M Feldman; Ignacio Garcia-De La Torre; Patrick Gordon; Taichi Hayashi; James D Katz; Hitoshi Kohsaka; Peter A Lachenbruch; Bianca A Lang; Yuhui Li; Chester V Oddis; Marzena Olesinska; Ann M Reed; Lidia Rutkowska-Sak; Helga Sanner; Albert Selva-O'Callaghan; Yeong-Wook Song; Jiri Vencovsky; Steven R Ytterberg; Frederick W Miller; Lisa G Rider Journal: Ann Rheum Dis Date: 2017-10-27 Impact factor: 19.103