Mechanism of CD79A and CD79B Support for IgM+ B Cell Fitness through B Cell Receptor Surface Expression [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Key Points

High surface expression of IgM protects against apoptosis in human GC B cells.

CD79A/B depletion resulted in loss of IgM surface expression and reduced fitness.

Glycan maturation of BCR complex components was interrupted upon CD79A or CD79B KO.

Visual AbstractFigureFigureAbstract

The BCR consists of surface-bound Ig and a heterodimeric signaling unit comprised of CD79A and CD79B. Upon cognate Ag recognition, the receptor initiates important signals for B cell development and function. The receptor also conveys Ag-independent survival signals termed tonic signaling. Although the requirement of a CD79A/CD79B heterodimer for BCR complex assembly and surface expression is well established based on mice models, few studies have investigated this in human mature B cells. In this study, we found that human tonsillar B cells with high surface expression of IgM or IgG had potentiated BCR signaling compared with BCRlow cells, and high IgM expression in germinal center B cells was associated with reduced apoptosis. We explored the mechanism for IgM surface expression by CRISPR/Cas9-induced deletion of CD79A or CD79B in four B lymphoma cell lines. Deletion of either CD79 protein caused loss of surface IgM in all cell lines and reduced fitness in three. From two cell lines, we generated stable CD79A or CD79B knockout clones and demonstrated that loss of CD79A or CD79B caused a block in N-glycan maturation and accumulation of immature proteins, compatible with retention of BCR components in the endoplasmic reticulum. Rescue experiments with CD79B wild-type restored surface expression of CD79A and IgM with mature glycosylation, whereas a naturally occurring CD79B G137S mutant disrupting CD79A/CD79B heterodimerization did not. Our study highlights that CD79A and CD79B are required for surface IgM expression in human B cells and illuminates the importance of the IgM expression level for signaling and fitness.

Footnotes

This work was supported by Norwegian Cancer Society Grants 16294 (Career Development Grant; to K.H.), 163260 (to J.H.M.), and 182694 (to E.B.S.), South-Eastern Norway Regional Health Authority Grant 2014075 (to E.B.S.), K.G. Jebsen Foundation Grant MED019 (to E.B.S. and J.H.M.), and by National Institutes of Health Grant R01 CA226833 (to J.M.I.).

The online version of this article contains supplemental material.

Abbreviations used in this article:

DLBCLdiffuse large B cell lymphomaEndo Hendoglycosidase HERendoplasmic reticulumGCgerminal centerGCBGC B cell–likeKOknockoutMCLmantle cell lymphomaPFAparaformaldehydephospho-flowphospho-specific flow cytometryPLCphospholipase CsgRNAsingle-guide RNAshRNAshort hairpin RNAWTwild-typeReceived February 18, 2022.Accepted September 9, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

留言 (0)

沒有登入
gif