Functional role for IκBNS in T cell cytokine regulation as revealed by targeted gene disruption

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

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1681-1692
Number of pages12
JournalJournal of Immunology
Volume179
Issue number3
DOIs
StatePublished - Aug 1 2007

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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