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NF-B1 p105 Regulates T Cell Homeostasis and Prevents Chronic Inflammation¹

Mikyoung Chang^2,*, Andrew J. Lee^2,*,, Leo Fitzpatrick, Minying Zhang^* and Shao-Cong Sun^3,*

^* Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston TX 77030; Department of Microbiology and Immunology and Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA 17033

Transcription factor NF-B is regulated by a family of inhibitors, IBs, as well as the NF-B1 and NF-B2 precursor proteins, p105 and p100. Although the different NF-B inhibitors can all inhibit NF-B in vitro, their physiological functions are incompletely understood. In this study, we demonstrate that p105 plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. Mice lacking p105, but expressing the mature NF-B1 p50, spontaneously develop intestinal inflammation with features of human inflammatory bowel disease. This inflammatory disorder occurs under specific pathogen-free conditions and critically involves T cells. Consistently, the p105-deficient mice have reduced frequency of naive T cells and increased frequency of memory/effector T cells in the peripheral lymphoid organs. Although p105 is dispensable for the production of immunosuppressive regulatory T cells, p105 deficiency renders CD4 T cells more resistant to Treg-mediated inhibition. We further show that the loss of p105 results in hyperproduction of Th17 subset of inflammatory T cells. Together, these findings suggest a critical role for NF-B1 p105 in the regulation of T cell homeostasis and differentiation and the control of chronic inflammation.

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 study was supported by grants from National Institutes of Health (AI064639, GM084459, and AI057555) and start-up fund from the University of Texas MD Anderson Cancer Center.

² M.C. and A.J.L. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Shao-Cong Sun, Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston TX 77030. E-mail address: ssun{at}mdanderson.org

⁴ Abbreviations used in this paper: Treg, regulatory T cell; IBD, inflammatory bowel disease; ICS, intracellular cytokine staining; WT, wild type; EMSA, Electrophoresis mobility shift assay; CD62L, CD62 ligand; mLN, mesentery lymph nodes.

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The JI 2009 182: 2555-2556. [Full Text]