The Cytoplasmic Domain of Igα Is Necessary and Sufficient to Support Efficient Early B Cell Development

Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
The Journal of Immunology (Impact Factor: 4.92). 03/2004; 172(4):2210-8.
Source: PubMed


The B cell receptor complex (BcR) is essential for normal B lymphocyte function, and surface BcR expression is a crucial checkpoint in B cell development. However, functional requirements for chains of the BcR during development remain controversial. We have used retroviral gene transfer to introduce components of the BcR into chicken B cell precursors during embryonic development. A chimeric heterodimer, in which the cytoplasmic domains of chicken Igalpha and Igbeta are expressed by fusion with the extracellular and transmembrane domains of murine CD8alpha and CD8beta, respectively, targeted the cytoplasmic domains of the BcR to the cell surface in the absence of extracellular BcR domains. Expression of this chimeric heterodimer supported all early stages of embryo B cell development: bursal colonization, clonal expansion, and induction of repertoire diversification by gene conversion. Expression of the cytoplasmic domain of Igalpha, in the absence of the cytoplasmic domain of Igbeta, was not only necessary, but sufficient to support B cell development as efficiently as the endogenous BcR. In contrast, expression of the cytoplasmic domain of Igbeta in the absence of the cytoplasmic domain of Igalpha failed to support B cell development. The ability of the cytoplasmic domain of Igalpha to support early B cell development required a functional Igalpha immunoreceptor tyrosine-based activation motif. These results support a model in which expression of surface IgM following productive V(D)J recombination in developing B cell precursors serves to chaperone the cytoplasmic domain of Igalpha to the B cell surface, thereby initiating subsequent stages of development.

5 Reads
  • Source
    • "Knockout mouse studies have shown that both CD79a and CD79b are necessary for differentiation of pro-B to pre-B cells in response to antigen engagement of the BCR [41]. However, dimers of the CD79a/b or of CD79a/a cytoplasmic domains alone can induce tonic antigen-independent signaling in B cell progenitors to support early stage differentiation 42,43. Furthermore, cross-linking of CD79a in early lineage B-cells was sufficient to induce downstream tyrosine phosphorylation though the functional consequences were not explored [44]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of myeloid derived suppressor cells (MDSCs) in promoting tumorigenesis is well-established, and significant effort is being made to further characterize surface markers on MDSCs both for better diagnosis and as potential targets for therapy. Here we show that the B cell receptor adaptor molecule CD79a is unexpectedly expressed on immature bone marrow myeloid cells, and is upregulated on MDSCs generated in multiple different mouse models of metastatic but not non-metastatic cancer. CD79a on MDSCs is upregulated and activated in response to soluble factors secreted by tumor cells. Activation of CD79a on mouse MDSCs, by crosslinking with a specific antibody, maintained their immature phenotype (CD11b+Gr1+), enhanced their migration, increased their suppressive effect on T cell proliferation, and increased secretion of pro-tumorigenic cytokines such as IL-6 and CCL22. Furthermore, crosslinking CD79a on myeloid cells activated signaling through Syk, BLNK, ERK and STAT3 phosphorylation. In vivo, CD79+ myeloid cells showed enhanced ability to promote primary tumor growth and metastasis. Finally we demonstrate that CD79a is upregulated on circulating myeloid cells from lung cancer patients, and that CD79a+ myeloid cells infiltrate human breast tumors. We propose that CD79a plays a functional role in the tumor promoting effects of myeloid cells, and may represent a novel target for cancer therapy.
    PLoS ONE 10/2013; 8(10):e76115. DOI:10.1371/journal.pone.0076115 · 3.23 Impact Factor
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Surface Ig (sIg) expression is a critical checkpoint during avian B cell development. Only cells that express sIg colonize bursal follicles, clonally expand, and undergo Ig diversification by gene conversion. Expression of a heterodimer, in which the extracellular and transmembrane domains of marine CD8α or CD8β are fused to the cytoplasmic domains of chicken Igα (chIgα) or Igβ, respectively (murine CD8α (mCD8α):chIgα + mCD8β:chIgβ), or an mCD8α: chIgα homodimer supported bursal B cell development as efficiently as endogenous sIg. In this study we demonstrate that B cell development, in the absence of chIgβ, requires both the Igα ITAM and a conserved non-ITAM Igα tyrosine (Y3) that has been associated with binding to B cell linker protein (BLNK). When associated with the cytoplasmic domain of Igβ, the Igα ITAM is not required for the induction of strong calcium mobilization or BLNK phosphorylation, but is still necessary to support B cell development. In contrast, mutation of the Igα Y3 severely compromised calcium mobilization when expressed as either a homodimer or a heterodimer with the cytoplasmic domain of Igβ. However, coexpression of the cytoplasmic domain of Igβ partially complemented the Igα Y3 mutation, rescuing higher levels of BLNK phosphorylation and, more strikingly, supporting B cell development.
    The Journal of Immunology 02/2005; 174(4). DOI:10.4049/jimmunol.174.4.2012 · 4.92 Impact Factor
Show more