CTLA-4 expression by B-1a B cells is essential for immune tolerance
Yang Yang, Xiao Li, Zhihai Ma, Chunlin Wang, Qunying Yang, Miranda Byrne‐Steele, Rongjian Hong, Qing Min, Gao Zhou, Yong Cheng, Qin Guang, Justin Youngyunpipatkul, James B. Wing, Shimon Sakaguchi, Christian Toonstra, Lai‐Xi Wang, José G. Vilches-Moure, Denong Wang, M Snyder, Jiyang Wang, Jian Han, Leonore A. Herzenberg
Abstract
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.