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Negative Regulation of TCR Signaling by NF-B2/p100¹

Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029

The positive regulation of the NF-B-signaling pathway in response to TCR stimulation has been well-studied. However, little is known about the negative regulation of this pathway in T cells. This negative regulation is crucial in controlling the duration of TCR signaling and preventing abnormal lymphocyte activation and proliferation. Therefore, understanding the negative regulation of TCR-mediated NF-B signaling is essential in understanding the mechanisms involved in T cell function and homeostasis. TCR stimulation of human CD4⁺ T cells resulted in an increase in NF-B2/p100 expression with no appreciable increase in p52, its cleavage product. Due to the presence of inhibitory ankyrin repeats in the unprocessed p100, this observation suggests that p100 may function as a negative regulator of the NF-B pathway. Consistent with this hypothesis, ectopic expression of p100 inhibited TCR-mediated NF-B activity and IL-2 production in Jurkat T cells. Conversely, knockdown of p100 expression enhanced NF-B transcriptional activity and IL-2 production upon TCR activation. p100 inhibited the pathway by binding and sequestering Rel transcription factors in the cytoplasm without affecting the activity of the upstream IB kinase. The kinetics and IB kinase /NF-B essential modulator dependency of p100 induction suggest that NF-B2/p100 acts as a late-acting negative-feedback signaling molecule in the TCR-mediated NF-B pathway.

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.

¹ This work was supported by National Institutes of Health Grants AI57997 and AI52417 (to A.T.T.). A.T.T. was supported by a research award from the Arthritis Foundation.

² Address correspondence and reprint requests to Dr. Adrian T. Ting, Immunology Institute, Mount Sinai School of Medicine, Box 1630, One Gustave L. Levy Place, New York, NY 10029. E-mail address: adrian.ting{at}mssm.edu

³ Abbreviations used in this paper: PTK, protein tyrosine kinase; PKC, protein kinase C; IKK, IB kinase; NEMO, NF-B essential modulator; NIK, NF-B-inducing kinase; RE, responsive element; SED, staphylococcal enterotoxin D; SEB, staphylococcal enterotoxin B; siRNA, small-interfering RNA; shRNA, short hairpin RNA.

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