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Functional Role for IBNS in T Cell Cytokine Regulation As Revealed by Targeted Gene Disruption¹

Maki Touma^*,, Valeria Antonini^*,, Manoj Kumar^2,*,, Stephanie L. Osborn^3,*, April M. Bobenchik^4,*, Derin B. Keskin^*,, John E. Connolly, Michael J. Grusby, Ellis L. Reinherz^*, and Linda K. Clayton^5,*,

^* Laboratory of Immunobiology, Department of Medical Oncology, Dana Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115; Baylor Institute for Immunology Research, Dallas, TX 75204; and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115

Triggering of the TCR by cognate peptide/MHC ligands induces expression of IBNS, a member of the IB family of NF-B inhibitors whose expression is associated with apoptosis of immature thymocytes. To understand the role of IBNS in TCR triggering, we created a targeted disruption of the IBNS gene. Surprisingly, mice lacking IBNS show normal thymic progression but both thymocytes and T cells manifest reduced TCR-stimulated proliferation. Moreover, IBNS knockout thymocytes and T cells produce significantly less IL-2 and IFN- than wild-type cells. Transfection analysis demonstrates that IBNS and c-Rel individually increase IL-2 promoter activity. The effect of IBNS on the IL-2 promoter, unlike c-Rel, is dependent on the NF-B rather than the CD28RE site; mutation of the NF-B site extinguishes the induction of transcription by IBNS in transfectants and prevents association of IBNS with IL-2 promoter DNA. Microarray analyses confirm the reduction in IL-2 production and some IFN--linked transcripts in IBNS knockout T cells. Collectively, our findings demonstrate that IBNS regulates production of IL-2 and other cytokines induced via "strong" TCR ligation.

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 AI19807 (to E.L.R.) and AI51779 (to L.K.C.).

² Current address: Beth Israel Deaconess Medical Center Genomic Center, Department of Medicine, Harvard Medical School, Boston, MA 02115.

³ Current address: Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California, Berkeley, CA 94720.

⁴ Current address: Center for Vascular Biology, University of Connecticut Health Center, Farmington, CT 06030.

⁵ Address correspondence and reprint requests to Dr. Linda K. Clayton, Dana Farber Cancer Institute, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: linda_clayton{at}dfci.harvard.edu

⁶ Abbreviations used in this paper: pMHC, peptide-MHC complex; DP, double positive; DN, double negative; LN, lymph node; WT, wild type; KO, knockout; BM, bone marrow; FC, fold change; rh, recombinant human; SAP, SLAM-associated protein.

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The JI 2007 179: 1411-1412. [Full Text]