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B Induction in Postdifferentiation IFN-
Production and Clonal Expansion in a Th1 Response1
* Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232; and
Department of Microbiology and Immunology, Meharry Medical College, Nashville, TN 37208.
NF-
B/Rel transcription factors are linked to innate immune responses and APC activation. Whether and how the induction of NF-B signaling in normal CD4+ T cells regulates effector function are not well-understood. The liberation of NF-B dimers from inhibitors of B (IBs) constitutes a central checkpoint for physiologic regulation of most forms of NF-B. To investigate the role of NF-B induction in effector T cell responses, we targeted inhibition of the NF-B/Rel pathway specifically to T cells. The Th1 response in vivo is dramatically weakened when T cells defective in their NF-B induction (referred to as IB
(
N) 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-B involves activation of the IFN-
gene in addition to clonal expansion efficiency. The role of NF-B in IFN- 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 IB-like protein, is decreased in T cells as a consequence of NF-B inhibition. Together, these findings indicate that NF-B induction in T cells regulates efficient clonal expansion, Th1 differentiation, and IFN- production by Th1 lymphocytes at a control point downstream from differentiation.
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