The Cross-Priming APC Requires a Rel-Dependent Signal to Induce CTL

Abstract

Induction of OVA-specific CTL by cross-priming requires help from CD4 T cells, which use CD154 to signal CD40 on the APC. To further dissect the molecular pathways involved in cross-priming, we examined the role of Rel, an NF-κB family member. c-rel−/− mice failed to generate OVA-specific CTL by cross-priming, but could induce CTL to HSV-1. Using chimeric mice, Rel expression was shown to be required by the APC, but not by the T cells. Notably, the deficiency in Rel could be overcome by triggering CD40, implying that the APC required Rel before receipt of the CD40 signal. These data suggest that the cross-priming APC must receive two signals before it can stimulate CTL. The first signal is Rel dependent and is required before activation of CD4 helper T cells, which then deliver the second signal using CD154 to trigger CD40.

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

“…Consistent with the findings demonstrating that c-Rel regulation of CD4 (Hilliard et al, 2002) and CD8 (Mintern et al, 2002) immune responses is mediated in part through its control of APC function, c-Rel serves a number of roles in different APC. c-rel À/À mice have reduced numbers of plasmacytoid DC (pDC) (O'Keeffe et al, 2005), the major producers of type I IFNs.…”

“…c-rel À/À mice have reduced numbers of plasmacytoid DC (pDC) (O'Keeffe et al, 2005), the major producers of type I IFNs. An absence of c-Rel does not affect conventional DC (cDC) development or the expression of co-stimulatory proteins on mature cDC (O'Keeffe et al, 2005), but c-Rel is necessary for these cells both to promote antigen-specific CTL responses by a mechanism of antigen crosspriming (Mintern et al, 2002) and to induce transcription of the IL-12 p35 gene (Grumont et al, 2001). This latter finding contrasts with a c-Rel requirement for p40 IL-12 subunit expression by macrophages (Sanjabi et al, 2000).…”

c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells

“…S6 A), the expansion of antigenstimulated OT-I CD8 T cells is equivalent in wt and c-rel / mice (Fig. S6 B; Mintern et al, 2002). Although these findings indicate that there are sufficient T reg cells that function relatively normally in c-rel / mice to prevent the development Current models of thymic T reg cell differentiation favor a multistep process controlled by TCR, costimulatory, and cytokine signals, each of which is required during specific stages of development (Liston and Rudensky, 2007).…”

Activation of NF-κB by the intracellular expression of NF-κB-inducing kinase acts as a powerful vaccine adjuvant

“…Nuclear localization of p65 and relB has been previously shown to correlate with DC maturation and efficient antigen presentation (29)(30)(31). The profound induction of both branches of NF-B activation by NIK results in the up-regulation of several antigenpresenting and costimulatory molecules, cytokines, and chemokines that contain NF-B sites in the promoters of their genes (32)(33)(34)(35)(36)(37).…”