CTLA-4 regulates T follicular regulatory cell differentiation and participates in intestinal damage caused by spontaneous autoimmunity

• Published in: Biochemical and biophysical research communications Vol. 505; no. 3; pp. 865 - 871
• Main Authors: Chao, Gao, Li, Xiaoli, Ji, Yahong, Zhu, Ying, Li, Na, Zhang, Nana, Feng, Zunyong, Niu, Min
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.11.2018
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; autoantibodies; Autoimmunity; B-lymphocytes; B-Lymphocytes - immunology; CD4-Positive T-Lymphocytes; CELL DIFFERENTIATION; CMV virus; Crohn disease; CTLA-4; CTLA-4 Antigen - deficiency; CTLA-4 Antigen - genetics; CTLA-4 Antigen - physiology; cytotoxicity; death; Follicular treg; Germinal Center; Humans; IBD; immune response; Immunity, Humoral; immunosuppression; INFLAMMATION; intestinal mucosa; Intestines - immunology; Intestines - pathology; LYMPHOCYTES; MICE; Murid betaherpesvirus 1; mutation; patients; T-Lymphocytes, Regulatory - cytology; VIRUSES; Autoimmunity; CTLA-4; IBD; Follicular treg; CMV virus
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2018.09.182

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a co-inhibitory molecule expressed by T cells and is required for immune regulation and inflammation prevention. In clinical patients, the CTLA-4 mutation causes spontaneous immune-related early-onset Crohn's disease; however, its potential mechanism is still unknown. In the current study, we found that defects in CTLA-4 in CD4 cells lead to limited differentiation of T follicular regulatory (Tfr) cells and relatively increased T follicular helper (Tfh) cells and spontaneous B cell germinal centres (GCs) responses that trigger the accumulation of autoantibodies in intestinal epithelial cells. In addition, the deficiency of Tfr cells caused by defects in CTLA-4 causes these cells to lose their function of inhibiting the non-specific immune response produced during the specific humoural immune response induced by MCMV (mouse cytomegalovirus), resulting in acute intestinal injury and death in mice. The lack of Tfr cells may be responsible for the immunosuppressive disorder of inflammatory bowel disease caused by CTLA-4 deficiency. In conclusion, we verified that CTLA-4 may be required for Tfr cell differentiation and production. Tfr cells inhibit B cell responses and prevent humoural autoimmune-mediated intestinal damage by regulating Tfh-dependent GC responses. •CTLA-4 deficiency leads to spontaneous humoural autoimmune intestinal injury.•CTLA-4 deficiency leads to differentiation obstacles in Tfr cells.•A Tfr shortage leads to non-specific humoural immunity enhancement.