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Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching

Manis, John P. and Gu, Yansong and Lansford, Rusty and Sonoda, Eiichiro and Ferrini, Roger and Davidson, Laurie and Rajewsky, Klaus and Alt, Frederick W. (1998) Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching. Journal of Experimental Medicine, 187 (12). pp. 2081-2089. ISSN 0022-1007. http://resolver.caltech.edu/CaltechAUTHORS:20120118-133507501

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Abstract

Immunoglobulin (Ig) heavy chain (HC) class switch recombination (CSR) is a late B cell process that involves intrachromosomal DNA rearrangement. Ku70 and Ku80 form a DNA end-binding complex required for DNA double strand break repair and V(D)J recombination. Ku70^(−/−) (K70T) mice, like recombination activating gene (RAG)-1– or RAG-2–deficient (R1T or R2T) mice, have impaired B and T cell development at an early progenitor stage, which is thought to result at least in part from defective V(D)J recombination (Gu, Y., K.J. Seidl, G.A. Rathbun, C. Zhu, J.P. Manis, N. van der Stoep, L. Davidson, H.L. Cheng, J.M. Sekiguchi, K. Frank, et al. 1997. Immunity. 7:653–665; Ouyang, H., A. Nussenzweig, A. Kurimasa, V.C. Soares, X. Li, C. Cordon-Cardo, W. Li, N. Cheong, M. Nussenzweig, G. Iliakis, et al. 1997. J. Exp. Med. 186:921–929). Therefore, to examine the potential role of Ku70 in CSR, we generated K70T mice that carry a germline Ig HC locus in which the JH region was replaced with a functionally rearranged VH(D)JH and Ig λ light chain transgene (referred to as K70T/HL mice). Previously, we have shown that B cells from R1T or R2T mice carrying these rearranged Ig genes (R1T/HL or R2T/HL mice) can undergo CSR to IgG isotypes (Lansford, R., J. Manis, E. Sonoda, K. Rajewsky, and F. Alt. 1998. Int. Immunol. 10:325–332). K70T/HL mice had significant numbers of peripheral surface IgM^+ B cells, which generated serum IgM levels similar to those of R2T/HL mice. However, in contrast to R2T/HL mice, K70T/HL mice had no detectable serum IgG isotypes. In vitro culture of K70T/HL B cells with agents that induce CSR in normal or R2T/HL B cells did lead to the induction of germline CH transcripts, indicating that initial signaling pathways for CSR were intact in K70T/HL cells. However, treatment with such agents did not lead to detectable CSR by K70T/HL B cells, and instead, led to cell death within 72 h. We conclude that Ku70 is required for the generation of B cells that have undergone Ig HC class switching. Potential roles for Ku70 in the CSR process are discussed


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1084/jem.187.12.2081DOIUNSPECIFIED
http://jem.rupress.org/content/187/12/2081.abstractPublisherUNSPECIFIED
Additional Information:© 1998 Rockefeller University Press. Submitted: 19 March 1998. We wish to thank M. Nussenzweig and colleagues for communication of unpublished results. This work was supported by the Howard Hughes Medical Institute, National Institutes of Health grants AI-240047 and AI-31541 (to F.W. Alt), and AI-01285 (to J.P. Manis), and a Deutsche Forschungsgemeinschaft grant (to K. Rajewsky). Y. Gu was supported in part by a fellowship from the Cancer Research Institute.
Funders:
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIHAI-240047
NIHAI-31541
NIHAI-01285
Deutsche ForschungsgemeinschaftUNSPECIFIED
Cancer Research InstituteUNSPECIFIED
Subject Keywords:immunoglobulin class switch recombination; Ku70; recombination activating gene 2; B cell development
Record Number:CaltechAUTHORS:20120118-133507501
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20120118-133507501
Official Citation:Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching John P. Manis, Yansong Gu, Rusty Lansford, Eiichiro Sonoda, Roger Ferrini, Laurie Davidson, Klaus Rajewsky, and Frederick W. Alt J Exp Med 1998 187:2081-2089. Published June 15, 1998, doi:10.1084/jem.187.12.2081
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:28836
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:18 Jan 2012 22:59
Last Modified:26 Dec 2012 14:42

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