T cell-intrinsic requirement for NF-κB induction in postdifferentiation IFN-γ production and clonal expansion in a Th1 response

NF-KB/Rel transcription factors are linked to innate immune responses and APC activation. Whether and how the induction of NF-KB signaling in normal CD4(+) T cells regulates effector function are not well-understood. The liberation of NF-KB dimers from inhibitors of KB (IKBs) constitutes a central checkpoint for physiologic regulation of most forms of NF-KB. To investigate the role of NF-KB induction in effector T cell responses, we targeted inhibition of the NF-KB/Rel pathway specifically to T cells. The Th1 response in vivo is dramatically weakened when T cells defective in their NF-KB induction (referred to as IKBalpha(DeltaN) transgenic cells) are activated by a normal APC population. Analyses in vivo, and IL-12-supplemented T cell cultures in vitro, reveal that the mechanism underlying this T cell-intrinsic requirement for NF-KB involves activation of the IFN-gamma gene in addition to clonal expansion efficiency. The role of NF-KB in IFN-gamma gene expression includes a modest decrease in Stat4 activation, T box expressed in T cell levels, and differentiation efficiency along with a more prominent postdifferentiation step. Further, induced expression of Bcl-3, a trans-activating IKB-like protein, is decreased in T cells as a consequence of NF-KB inhibition. Together, these findings indicate that NF-KB induction in T cells regulates efficient clonal expansion, Th1 differentiation, and IFN-gamma production by Th1 lymphocytes at a control point downstream from differentiation.