| Literature DB >> 33483505 |
Yang Yang1, Xiao Li2, Zhihai Ma3, Chunlin Wang4, Qunying Yang4, Miranda Byrne-Steele4, Rongjian Hong5, Qing Min5, Gao Zhou2, Yong Cheng6, Guang Qin3, Justin V Youngyunpipatkul3, James B Wing7,8, Shimon Sakaguchi8, Christian Toonstra9, Lai-Xi Wang9, Jose G Vilches-Moure10, Denong Wang11, Michael P Snyder3, Ji-Yang Wang5,12,13, Jian Han4,14, Leonore A Herzenberg15.
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.Entities:
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Year: 2021 PMID： 33483505 PMCID： PMC7822855 DOI： 10.1038/s41467-020-20874-x
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919