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J. Biol. Chem., Vol. 278, Issue 25, 23141-23150, June 20, 2003

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Selective Inhibition of Class Switching to IgG and IgE by Recruitment of the HoxC4 and Oct-1 Homeodomain Proteins and Ku70/Ku86 to Newly Identified ATTT cis-Elements^*,

András Schaffer   ¶, Edmund C. Kim  ¶ ||, Xiaoping Wu  ||, Hong Zan  ||, Lucia Testoni  **, Szilvia Salamon  ||, Andrea Cerutti  and Paolo Casali  || 

From the Division of Molecular Immunology, Department of Pathology and Laboratory Medicine, Joan and Sanford I. Weill Medical College, Cornell University, New York, New York 10021 and the ^||Center for Immunology, School of Biological Sciences and College of Medicine, University of California, Irvine, California 92697

Immunoglobulin (Ig) class switching is central to the maturation of the antibody response as IgG, IgA, and IgE are endowed with more diverse biological effector functions than IgM. It is induced upon engagement of CD40 on B lymphocytes by CD40L expressed by activated CD4⁺ T cells and exposure of B cells to T cell-secreted cytokines including interleukin-4 and transforming growth factor-. It begins with germ line I_H-C_H transcription and unfolds through class switch DNA recombination (CSR). We show here that the HoxC4 and Oct-1 homeodomain proteins together with the Ku70/Ku86 heterodimer bind as a complex to newly identified switch (S) regulatory ATTT elements (SREs) in the I and I promoters and downstream regions to dampen basal germ line I-C and I-C transcriptions and repress CSR to C and C. This mechanism is inactive in the C1/C2 loci because of the lack of SREs in the I1/I2 promoters. Accordingly, in resting human IgM⁺IgD⁺ B cells, HoxC4, Oct-1, and Ku70/Ku86 can be readily identified as bound to the I and I promoters but not the I1/I2 promoters. CD40 signaling dissociates the HoxC4·Oct-1·Ku complex from the I and I promoter SREs, thereby relieving the I_H-C_H transcriptional repression and allowing CSR to unfold. Dissociation of HoxC4·Oct-1·Ku from DNA is hampered by CD153 engagement, a CD40-signaling inhibitor. Thus, these findings outline a HoxC4·Oct-1·Ku-dependent mechanism of selective regulation of class switching to IgG and IgE and further suggest distinct co-evolution and shared CSR activation pathways in the C and C as opposed to the C1/C2 loci.

Received for publication, December 19, 2002 , and in revised form, March 20, 2003.

^* This work was supported in part by National Institutes of Health Grants AI 45011, AR 40908, AI 07621, and AG 13910 (to P. C.), a Cancer Research Institute predoctoral fellowship in tumor immunology (to A. S.), National Institutes of Health Grant AR 47872, and a New Investigator Award from the Leukemia Research Foundation (to A. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 2, A and B, and 7, A and B.

Present address: Dept. of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.

^¶ Both authors contributed equally to this work.

^** Present address: Dept. of Internal Medicine, University of Milan Medical School, Milano 20122, Italy.

To whom correspondence should be addressed. Tel.: 949-824-9648; E-mail: pcasali{at}uci.edu.

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