c‐Rel phenocopies PKCθ but not Bcl‐10 in regulating CD8⁺ T‐cell activation versus tolerance

Abstract

Elucidating the signaling events that promote T-cell tolerance versus activation provides important insights for manipulating immunity in vivo. Previous studies have suggested that the absence of PKCh results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-jB plays a key role in determining whether T-cell anergy or activation is induced. Here, we examine whether Bcl-10 and specific family members of NF-jB act downstream of PKCh to alter CD8 1 T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-jB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCh-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCh-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-jB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCh in controlling CD81 T-cell anergy induction.Key words: Anergy . CD8 1 T cells . NF-kB pathway . Tolerance IntroductionUnderstanding the signals that lead to T-cell tolerance versus activation has the potential to be clinically applicable for treatment of autoimmune diseases and promoting anti-tumor responses. Events associated with the induction of T-cell tolerance versus activation are thought to be determined during T-cell interactions with DC. Recognition of Ag together with costimulatory and proinflammatory signals are believed to elicit optimal T-cell activation.Although recent work has identified several molecules that are involved in influencing the anergic state [1,2], it remains unclear how different molecules are connected and integrated by the T cell to induce tolerance or activation. The serine/threonine Eur. J. Immunol. 2010. 40: 867-877 DOI 10.1002 Leukocyte signaling 867 kinase PKCy lies downstream of the TCR and is involved in the activation of NF-kB, AP-1 and NFAT [3][4][5]. Costimulatory signals through CD28 enhance both the recruitment of PKCy to the immunological synapse and its activation [6][7][8][9][10]. Furthermore, studies from several groups support a central role for PKCy in controlling T-cell activation versus anergy [11][12][13]. To further delineate a molecular pathway that is important for the induction of T-cell anergy versus activation, we wanted to examine the role of molecules downstream of PKCy. PKCy activates NF-kB via the CARMA/Bcl-10/MALT complex [14]. Like PKCy À/À T cells [3,4], the T lymphocytes from mice deficient in any of these three molecules show decreased NF-kB activation and have defects in activation and proliferation. The NF-kB family is composed of five members: c-Rel, RelA, RelB, NF-kB1 (p50/p105) and NF-kB2 (p52/p100). Some functions are unique to specific members of this family; for example, RelA deficiency is embryonic lethal due to apoptosis of fetal hepatocytes [15,16]. Significan...

The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells

“…This is suggested to occur in B cells, where MALT1 directs BCR-induced canonical NF-κB signaling selectively to the c-Rel subunit (28). Interestingly, for CD8 T-cell activation, c-Rel deficiency has been reported to phenocopy deficiency of PKCθ thought to activate the CARMA1, BCL10, and MALT1 signalosome, but not BCL10 deficiency (29). Irrespective of the detailed mechanism of increase in NF-κB activity, we show that A20 deletion in CD8 T cells greatly enhances their capacity to produce IL-2 and IFNγ.…”

B7/CD28 in Central Tolerance: Costimulation Promotes Maturation of Regulatory T Cell Precursors and Prevents Their Clonal Deletion

“…Mutations in the CD28 P 187 YAPP motif strongly diminish TCR/CD28 mediated NF-κB activation (Sanchez-Lockhart et al, 2008), and the ablation of genes involved in NF-κB activation (PKC-θ, CARMA-1, Bcl-10, IKK-2) impairs thymic T reg differentiation (Schmidt-Supprian et al, 2004; Barnes et al, 2009; Medoff et al, 2009). The recent identification of c-Rel as essential NF-κB family transcription factor in T reg differentiation may provide important clues as to how integrated TCR/CD28 signaling activates the transcriptional program that controls T reg differentiation (Isomura et al, 2009; Long et al, 2009; Ruan et al, 2009; Deenick et al, 2010; Visekruna et al, 2010). One aspect of c-Rel’s function seems to be direct control of the Foxp3 gene through binding to a DNA motif resembling the CD28-response element in the IL-2 gene (Zheng et al, 2010).…”

c‐Rel but not NF‐κB1 is important for T regulatory cell development

“…We recently reported that signalling for activation rather than anergy in CD8 1 T cells is also dependent on PKCy-Bcl-10-c-Rel signalling [21]. Thus, two distinct forms of tolerance induction, anergy induction and Treg generation, are controlled by the same pathway.…”

“…1 T-cell-Bcl-10 is more critical for CD8 1 T-cell activation than PKCy or c-Rel and that Bcl-10 deficiency results in a more severe defect in NF-kB activation [21]. In addition, the role of Bcl-10 is not limited to NF-kB activation, as it has also been shown to be involved in actin polymerization [22].…”