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, Guang Qin, Justin V. Youngyunpipatkul, James B. Wing, Shimon Sakaguchi, Christian Toonstra, Lai-Xi Wang, Jose G. Vilches-Moure, Denong Wang, Michael P. Snyder, Ji-Yang Wang, Jian Han and Leonore A. Herzenberg ()
Additional contact information
Yang Yang: Stanford University School of Medicine
Xiao Li: Case Western Reserve University
Zhihai Ma: Stanford University School of Medicine
Chunlin Wang: iRepertoire Inc
Qunying Yang: iRepertoire Inc
Miranda Byrne-Steele: iRepertoire Inc
Rongjian Hong: Fudan University
Qing Min: Fudan University
Gao Zhou: Case Western Reserve University
Yong Cheng: St. Jude Children’s Research Hospital
Guang Qin: Stanford University School of Medicine
Justin V. Youngyunpipatkul: Stanford University School of Medicine
James B. Wing: Osaka University
Shimon Sakaguchi: Osaka University
Christian Toonstra: University of Maryland
Lai-Xi Wang: University of Maryland
Jose G. Vilches-Moure: Stanford University School of Medicine
Denong Wang: SRI International Biosciences Division
Michael P. Snyder: Stanford University School of Medicine
Ji-Yang Wang: Fudan University
Jian Han: iRepertoire Inc
Leonore A. Herzenberg: Stanford University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20874-x

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