Journal Article

CTLA-4 expression by B-1a B cells is essential for immune tolerance

Sakaguchi, Shimon, Ma, Zhihai, Yang, Qunying, Cheng, Yong, Vilches-Moure, Jose G., Hong, Rongjian, Min, Qing, Snyder, Michael P., Yang, Yang, Toonstra, Christian, Han, Jian, Wang, Lai-Xi, Wang, Chunlin, Zhou, Gao, Youngyunpipatkul, Justin V., Wang, Ji-Yang, Wang, Denong, Li, Xiao, Byrne-Steele, Miranda, Wing, James B., Qin, Guang, Herzenberg, Leonore A.

2021

Overview

CTLA-4 is an important regulator of T-cell function. Here, we report that expression of this immune-regulator in mouse B-1a cells has a critical function in maintaining self-tolerance by regulating these early-developing B cells that express a repertoire enriched for auto-reactivity. Selective deletion of CTLA-4 from B cells results in mice that spontaneously develop autoantibodies, T follicular helper (Tfh) cells and germinal centers (GCs) in the spleen, and autoimmune pathology later in life. This impaired immune homeostasis results from B-1a cell dysfunction upon loss of CTLA-4. Therefore, CTLA-4-deficient B-1a cells up-regulate epigenetic and transcriptional activation programs and show increased self-replenishment. These activated cells further internalize surface IgM, differentiate into antigen-presenting cells and, when reconstituted in normal IgH-allotype congenic recipient mice, induce GCs and Tfh cells expressing a highly selected repertoire. These findings show that CTLA-4 regulation of B-1a cells is a crucial immune-regulatory mechanism. CTLA-4 is an important co-inhibitory receptor for T cells. Here, the authors show that CTLA-4 also has a function on B-1a cells, as conditional deletion results in activation of these cells and knockout mice develop an autoimmune profile.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/31 / 13/51 / 14 / 14/19 / 38 / 38/77 / 38/91 / 631/250/1619/40/1906 / 631/250/38 / 631/80/304 / Animals / Antigen-presenting cells / Antigens / Autoantibodies / B-Lymphocyte Subsets - immunology / B-Lymphocyte Subsets - metabolism / Cell activation / Cell differentiation / Cell Differentiation - immunology / Clonal deletion / CTLA-4 Antigen - genetics / CTLA-4 Antigen - immunology / CTLA-4 Antigen - metabolism / CTLA-4 protein / Deletion / Epigenetics / Germinal Center - cytology / Germinal Center - immunology / Germinal Center - metabolism / Germinal centers / Heavy chains / Homeostasis / Homeostasis - immunology / Humanities and Social Sciences / Immune System - cytology / Immune System - immunology / Immune System - metabolism / Immune Tolerance - immunology / Immunoglobulin M / Immunoglobulin M - blood / Immunoglobulin M - immunology / Immunological tolerance / Lymphocytes / Lymphocytes B / Lymphocytes T / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / multidisciplinary / Regulatory mechanisms (biology) / Replenishment / Rodents / Science / Science (multidisciplinary) / Spleen / T-Lymphocytes, Helper-Inducer - cytology / T-Lymphocytes, Helper-Inducer - immunology / T-Lymphocytes, Helper-Inducer - metabolism / Transcription activation