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PMID: 8294858 Published · ppublish English Journal Article

Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells.

The Journal of experimental medicine ·Vol. 179 ·No. 2 ·1994-02-01 ·Pages 425-38

Cooke MP, Heath AW, Shokat KM, Zeng Y, Finkelman FD, Linsley PS, Howard M, Goodnow CC

Abstract

The specificity of antibody (Ab) responses depends on focusing helper T (Th) lymphocyte signals to suitable B lymphocytes capable of binding foreign antigens (Ags), and away from nonspecific or self-reactive B cells. To investigate the molecular mechanisms that prevent the activation of self-reactive B lymphocytes, the activation requirements of B cells specific for the Ag hen egg lysozyme (HEL) obtained from immunoglobulin (Ig)-transgenic mice were compared with those of functionally tolerant B cells isolated from Ig-transgenic mice which also express soluble HEL. To eliminate the need for surface (s)Ig-mediated Ag uptake and presentation and allow the effects of sIg signaling to be studied in isolation, we assessed the ability of allogeneic T cells from bm12 strain mice to provide in vivo help to C57BL/6 strain-transgenic B cells. Interestingly, non-tolerant Ig-transgenic B cells required both allogeneic Th cells and binding of soluble HEL for efficient activation and Ab production. By contrast, tolerant self-reactive B cells from Ig/HEL double transgenic mice responded poorly to the same combination of allogeneic T cells and soluble HEL. The tolerant B cells were nevertheless normally responsive to stimulation with interleukin 4 and anti-CD40 Abs in vitro, suggesting that they retained the capacity to respond to mediators of T cell help. However, the tolerant B cells exhibited a proximal block in the sIg signaling pathway which prevented activation of receptor-associated tyrosine kinases in response to the binding of soluble HEL. The functional significance of this sIg signaling defect was confirmed by using a more potent membrane-bound form of HEL capable of triggering sIg signaling in tolerant B cells, which markedly restored their ability to collaborate with allogeneic Th cells and produce Ab. These findings indicate that Ag-specific B cells require two signals for mounting a T cell-dependent Ab response and identify regulation of sIg signaling as a mechanism for controlling self-reactive B cells.

MeSH Terms
Animals Antigens/immunology B-Lymphocytes/immunology,metabolism,physiology Cell Communication Cell Membrane/enzymology Cells, Cultured Immune Tolerance Immunoglobulin D/immunology Immunoglobulin M/immunology Mice Mice, Inbred C57BL Mice, Transgenic Muramidase/metabolism Receptors, Antigen, B-Cell/metabolism Signal Transduction T-Lymphocytes/immunology,metabolism,physiology
Chemicals
Antigens Immunoglobulin D Immunoglobulin M Receptors, Antigen, B-Cell Muramidase
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Cooke M P
Howard Hughes Medical Institute, Stanford University, California 94305.
Heath A W
Shokat K M
Zeng Y
Finkelman F D
Linsley P S
Howard M
Goodnow C C
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.179.2.425
Published
1994-02-01
Pages
425-38
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2191355
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.179.2.425 PMC Full Text View journal details
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