Cooke, M.P., Heath, A.W., Shokat, K.M. et al. (5 more authors) (1994) Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. Journal of Experimental Medicine, 179 (2). pp. 425-438. ISSN 0022-1007
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 1994 Rockefeller University Press. Reproduced in accordance with the publisher's self-archiving policy. |
Keywords: | LYMPHOCYTES-B; TYROSINE PHOSPHORYLATION; ACTIVATION ANTIGEN-B7; COSTIMULATORY SIGNAL; CROSS-LINKING; SURFACE-IMMUNOGLOBULIN; TRANSGENIC MICE; IMMUNE-SYSTEM; FC-RECEPTORS; ANTI-IG |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Infection, Immunity and Cardiovascular Disease The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Sep 2016 12:38 |
Last Modified: | 23 Jun 2023 21:43 |
Published Version: | http://dx.doi.org/10.1084/jem.179.2.425 |
Status: | Published |
Publisher: | Rockefeller University Press |
Refereed: | Yes |
Identification Number: | 10.1084/jem.179.2.425 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:81900 |