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B cell peripheral tolerance is promoted by cathepsin B protease
Marissa Y Chou1,2, Dan Liu1,2, Jinping An1,2
1Department of Microbiology and Immunology, University of California, San Francisco, CA 94143.
Summary
Cathepsin B (Ctsb) promotes the elimination of B cells that bind self-antigens. Ctsb deficiency improves B cell survival, revealing a new checkpoint for peripheral self-tolerance.
Area of Science:
- Immunology
- Molecular Biology
Background:
- B cells binding soluble autoantigens face chronic B cell receptor signaling (signal-1) without costimulation (signal-2), leading to elimination.
- The precise mechanisms governing this elimination remain incompletely understood.
Purpose of the Study:
- To investigate the role of cathepsin B (Ctsb) in the elimination of self-reactive B cells.
- To elucidate the factors influencing B cell survival under chronic antigen exposure.
Main Methods:
- Utilized hen egg lysozyme-specific (HEL-specific) immunoglobulin transgenic (MD4) B cells and mice with circulating HEL.
- Employed bone marrow chimera experiments to assess hematopoietic and nonhematopoietic contributions of Ctsb.
- Investigated the impact of CD4+ T cell depletion and CD40/CD40L blockade on B cell survival.
Main Results:
- Ctsb deficiency significantly improved the survival and proliferation of HEL-binding B cells.
- Both hematopoietic and nonhematopoietic Ctsb were sufficient to promote peripheral B cell deletion.
- Depletion of CD4+ T cells or blockade of CD40L signaling reversed the survival advantage in Ctsb-deficient mice.
Conclusions:
- Cathepsin B (Ctsb) acts extracellularly to limit the survival of B cells recognizing soluble autoantigens.
- Ctsb restrains CD40L-dependent pro-survival signals, establishing a peripheral self-tolerance checkpoint.
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