T Cell-Intrinsic Requirement for NF-κB Induction in Postdifferentiation IFN-γ Production and Clonal Expansion in a Th1 Response

Abstract

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

The negative regulators Foxj1 and Foxo3a are up‐regulated by a peptide that inhibits systemic lupus erythematosus‐associated T cell responses

“…Therefore, the inhibition of IFN-c secretion probably does not reflect enhanced Th2 stimulation. Further, the inhibitory effect of hCDR1 on IFN-c did not result in upregulated IL-17 mRNA expression, but rather the latter was down-regulated by about threefold (unpublished results) NF-jB is a transcription factor that has been shown to control the amount of IFN-c produced by a differentiated Th1 population [22]. Its main activated form is a heterodimer of p65 subunit that translocates to the nucleus [23], where it activates the expression of many genes including IFN-c.…”

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…The number of peripheral T cells, in particular CD8 þ cells, is markedly reduced (Boothby et al, 1997;Hettmann et al, 1999) and their functional responses are impaired, the extent and nature of which appears to be transgene strain dependent. These include reduced proliferation by CD4 þ and CD8 þ T cells (Aune et al, 1999;Mora et al, 2003), plus defects in the development, expansion and cytokine production by Th1 effectors (Aronica et al, 1999;Aune et al, 1999;Corn et al, 2003). In turn, these defects have effects on delayed-type hypersensitivity responses, IgG2a production (Aronica et al, 1999), the clearance of pathogens such as T. gondii (Tato et al, 2003) and allograft rejection (Finn et al, 2001).…”

Activation of NF-κB1 by OX40 Contributes to Antigen-Driven T Cell Expansion and Survival

“…Similarly, also in NF-B1 knockout mice, Ag-specific CD4 T cell proliferation and IFN-␥ production were impaired following infection with the intracellular protozoan parasite Leishmania major (25). In line with a role in Th1 responses, mice transgenic for a superrepressor IB␣, expressed in T cells, were defective in delayedtype hypersensitivity responses and IFN-␥ production, but mounted normal Th2 responses (26,27). Of further interest, tolerant T cells that fail to produce IL-2 have been associated with a predominance of p50-p50 homodimers that bind to the IL-2 promoter B site, correlating with repressed activity of NF-B-driven transcription (28).…”