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J. Biol. Chem., Vol. 279, Issue 9, 8460-8468, February 27, 2004

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Bcl-3 and NFB p50-p50 Homodimers Act as Transcriptional Repressors in Tolerant CD4⁺ T Cells^*

Susanna Grundström¶, Per Anderson||, Peter Scheipers, and Anette Sundstedt

From the Active Biotech Research Center, Scheelevägen 22, S-223 63 Lund, Sweden and the Sections for Immunology, Biomedical Center I:13 and ^||Tumor Immunology, Biomedical Center I:12, Department of Cell and Molecular Biology, Lund University, S-221 84 Lund, Sweden

The transcriptional events that control T cell tolerance are still poorly understood. To investigate why tolerant T cells fail to produce interleukin (IL)-2, we analyzed the regulation of NFB-mediated transcription in CD4⁺ T cells after tolerance induction in vivo. We demonstrate that a predominance of p50-p50 homodimers binding to the IL-2 promoter B site in tolerant T cells correlated with repression of NFB-driven transcription. Impaired translocation of the p65 subunit in tolerant T cells was a result from reduced activation of IB kinase and poor phosphorylation and degradation of cytosolic IBs. Moreover, tolerant T cells expressed high amounts of the p50 protein. However, the increased expression of p50 could not be explained by activation-induced de novo synthesis of the precursor p105, which was constitutively expressed in tolerant T cells. We also demonstrate the exclusive induction of the IB protein B cell lymphoma 3 (Bcl-3) in tolerant T cells as well as its specific binding to the NFB site. These results suggest that the cellular ratio of NFB dimers, and thus the repression of NFB activity and IL-2 production, are regulated at several levels in tolerant CD4⁺ T cells in vivo.

Received for publication, November 12, 2003

^* This work was partly supported by grants from the Swedish Cancer Society. 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.

^¶ To whom correspondence should be addressed: Center for Infectious Medicine, F59, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. Tel.: 46-8-5858-2276; Fax: 46-8-746-7637; E-mail: susanna. grundstrom{at}medhs.ki.se.

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