Ku70 Is Required for Late B Cell Development and Immunoglobulin Heavy Chain Class Switching
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
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 We wish to thank M. Nussenzweig and colleagues for communication of unpublished results.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.Attached Files
Published - MANjem98.pdf
Files
Name | Size | Download all |
---|---|---|
md5:83e24867971031006cc7cc424bc61a6a
|
218.8 kB | Preview Download |
Additional details
- PMCID
- PMC2212369
- Eprint ID
- 28836
- Resolver ID
- CaltechAUTHORS:20120118-133507501
- Howard Hughes Medical Institute (HHMI)
- AI-240047
- NIH
- AI-31541
- NIH
- AI-01285
- NIH
- Deutsche Forschungsgemeinschaft (DFG)
- Cancer Research Institute
- Created
-
2012-01-18Created from EPrint's datestamp field
- Updated
-
2021-11-09Created from EPrint's last_modified field