Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
HHMI, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2300099120. doi: 10.1073/pnas.2300099120. Epub 2023 Apr 11.
B cells that bind soluble autoantigens receive chronic signaling via the B cell receptor (signal-1) in the absence of strong costimulatory signals (signal-2), and this leads to their elimination in peripheral tissues. The factors determining the extent of soluble autoantigen-binding B cell elimination are not fully understood. Here we demonstrate that the elimination of B cells chronically exposed to signal-1 is promoted by cathepsin B (Ctsb). Using hen egg lysozyme-specific (HEL-specific) immunoglobulin transgenic (MD4) B cells and mice harboring circulating HEL, we found improved survival and increased proliferation of HEL-binding B cells in Ctsb-deficient mice. Bone marrow chimera experiments established that both hematopoietic and nonhematopoietic sources of Ctsb were sufficient to promote peripheral B cell deletion. The depletion of CD4 T cells overcame the survival and growth advantage provided by Ctsb deficiency, as did blocking CD40L or removing CD40 from the chronically antigen-engaged B cells. Thus, we suggest that Ctsb acts extracellularly to reduce soluble autoantigen-binding B cell survival and that its actions restrain CD40L-dependent pro-survival effects. These findings identify a role for cell-extrinsic protease activity in establishing a peripheral self-tolerance checkpoint.
B 细胞结合可溶性自身抗原后，在缺乏强共刺激信号（信号 2）的情况下，通过 B 细胞受体（信号 1）持续接受信号，这导致它们在外周组织中被消除。决定可溶性自身抗原结合 B 细胞消除程度的因素尚未完全阐明。在这里，我们证明了持续暴露于信号 1 的 B 细胞的消除是由组织蛋白酶 B（Ctsb）促进的。使用鸡卵溶菌酶特异性（HEL 特异性）免疫球蛋白转基因（MD4）B 细胞和携带循环 HEL 的小鼠，我们发现 Ctsb 缺陷小鼠中 HEL 结合 B 细胞的存活率提高和增殖增加。骨髓嵌合体实验确立了造血和非造血来源的 Ctsb 均足以促进外周 B 细胞的删除。耗尽 CD4 T 细胞克服了 Ctsb 缺乏提供的生存和生长优势，就像阻断 CD40L 或从慢性抗原结合的 B 细胞中去除 CD40 一样。因此，我们认为 Ctsb 作为细胞外物质起作用，以降低可溶性自身抗原结合 B 细胞的存活率，并且其作用抑制了 CD40L 依赖性的促生存作用。这些发现确定了细胞外蛋白酶活性在建立外周自身耐受检查点中的作用。
