Functional Role for IκBNS in T Cell Cytokine Regulation As Revealed by Targeted Gene Disruption

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.