The Journal of Experimental Medicine
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Published online 27 December 2005 doi:10.1084/jem.20051450
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 1, 63-72
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ARTICLE

 Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein

Chang Hoon Lee1, Mark Melchers2, Hongsheng Wang1, Ted A. Torrey1, Rebecca Slota2, Chen-Feng Qi1, Ji Young Kim4, Patricia Lugar2, Hee Jeong Kong4, Lila Farrington2, Boris van der Zouwen2, Jeff X. Zhou1, Vassilios Lougaris2, Peter E. Lipsky3, Amrie C. Grammer2, and Herbert C. Morse, III1

1 Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, 2 B Cell Biology Group and 3 Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and 4 Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

CORRESPONDENCE: Amrie C. Grammer: grammera{at}mail.nih.gov OR Herbert C. Morse III: hmorse{at}niaid.nih.gov

Interferon (IFN) consensus sequence-binding protein/IFN regulatory factor 8 (IRF8) is a transcription factor that regulates the differentiation and function of macrophages, granulocytes, and dendritic cells through activation or repression of target genes. Although IRF8 is also expressed in lymphocytes, its roles in B cell and T cell maturation or function are ill defined, and few transcriptional targets are known. Gene expression profiling of human tonsillar B cells and mouse B cell lymphomas showed that IRF8 transcripts were expressed at highest levels in centroblasts, either from secondary lymphoid tissue or transformed cells. In addition, staining for IRF8 was most intense in tonsillar germinal center (GC) dark-zone centroblasts. To discover B cell genes regulated by IRF8, we transfected purified primary tonsillar B cells with enhanced green fluorescent protein–tagged IRF8, generated small interfering RNA knockdowns of IRF8 expression in a mouse B cell lymphoma cell line, and examined the effects of a null mutation of IRF8 on B cells. Each approach identified activation-induced cytidine deaminase (AICDA) and BCL6 as targets of transcriptional activation. Chromatin immunoprecipitation studies demonstrated in vivo occupancy of 5' sequences of both genes by IRF8 protein. These results suggest previously unappreciated roles for IRF8 in the transcriptional regulation of B cell GC reactions that include direct regulation of AICDA and BCL6.

Abbreviations used: AICDA, activation-induced cytidine deaminase; CB, centroblastic; ChIP, chromatin immunoprecipitation; CSR, class switch recombination; EGFP, enhanced GFP; EICE, Ets/IRF composite element; GC, germinal center; ICSBP, IFN consensus sequence-binding protein; IRF, IFN regulatory factor; PBB, peripheral blood B cell; qPCR, quantitative RT-PCR; SHM, somatic hypermutation; siRNA, small interfering RNA.

C.H. Lee and M. Melchers contributed equally to this work.


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