c-Rel phenocopies PKCtheta but not Bcl-10 in regulating CD8+ T-cell activation versus tolerance.
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 PKCtheta results in the induction of anergy and that the balance between the induction of the transcription factors NFAT, AP1 and NF-kappaB 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-kappaB act downstream of PKCtheta to alter CD8(+) T-cell activation and/or anergy. We showed that T cells from mice deficient in c-Rel but not NF-kappaB1 (p50) have increased susceptibility to the induction of anergy, similar to T cells from PKCtheta-deficient mice. Surprisingly T cells from Bcl-10-deficient mice showed a strikingly different phenotype to the PKCtheta-deficient T cells, with a severe block in TCR-mediated activation. Furthermore, we have also shown that survival signals downstream of NF-kappaB, are uncoupled from signals that mediate T-cell anergy. These results suggest that c-Rel plays a critical role downstream of PKCtheta in controlling CD8(+) T-cell anergy induction.
Deenick
Elissa K
EK
Campbell Family Institute, Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada. e.deenick@garvan.org.au
Po
Leslie
L
Chapatte
Laurence
L
Murakami
Kiichi
K
Lu
Yong-Chen
YC
Elford
Alisha R
AR
Saibil
Samuel D
SD
Ruland
Jürgen
J
Gerondakis
Steve
S
Mak
Tak W
TW
Ohashi
Pamela S
PS
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology*; D007527:Isoenzymes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000276:immunology; D010641:Phenotype; D011493:Protein Kinase C / Q000276:immunology*; D000074121:Protein Kinase C-theta; D020569:Proto-Oncogene Proteins c-rel / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D007527:Isoenzymes; D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta