T cell-intrinsic requirement for NF-kappa B induction in postdifferentiation IFN-gamma production and clonal expansion in a Th1 response.

Corn RA, Aronica MA, Zhang F, Tong Y, Stanley SA, Kim SR, Stephenson L, Enerson B, McCarthy S, Mora A, Boothby M
J Immunol. 2003 171 (4): 1816-24

PMID: 12902482 · DOI:10.4049/jimmunol.171.4.1816

NF-kappaB/Rel transcription factors are linked to innate immune responses and APC activation. Whether and how the induction of NF-kappaB signaling in normal CD4(+) T cells regulates effector function are not well-understood. The liberation of NF-kappaB dimers from inhibitors of kappaB (IkappaBs) constitutes a central checkpoint for physiologic regulation of most forms of NF-kappaB. To investigate the role of NF-kappaB induction in effector T cell responses, we targeted inhibition of the NF-kappaB/Rel pathway specifically to T cells. The Th1 response in vivo is dramatically weakened when T cells defective in their NF-kappaB induction (referred to as IkappaBalpha(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-kappaB involves activation of the IFN-gamma gene in addition to clonal expansion efficiency. The role of NF-kappaB 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 IkappaB-like protein, is decreased in T cells as a consequence of NF-kappaB inhibition. Together, these findings indicate that NF-kappaB induction in T cells regulates efficient clonal expansion, Th1 differentiation, and IFN-gamma production by Th1 lymphocytes at a control point downstream from differentiation.

MeSH Terms (19)

Adoptive Transfer Animals Cell Differentiation Cells, Cultured Clone Cells I-kappa B Proteins Interferon-gamma Mice Mice, Inbred BALB C Mice, Transgenic NF-kappa B NF-KappaB Inhibitor alpha Proto-Oncogene Proteins T-Box Domain Proteins T-Lymphocyte Subsets Th1 Cells Transcription Factor RelA Transcription Factors Transgenes

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