PKC theta cooperates with PKC alpha in alloimmune responses of T cells in vivo.
The physiological roles of PKC alpha and PKC theta were defined in T cell immune functions downstream of the antigen receptor. To investigate the hypothesis that both PKC isotypes may have overlapping functions, we generated mice lacking both genes. We find that PKC alpha(-/-)/theta(-/-) animals have additive T cell response defects in comparison to animals carrying single mutations in these genes. Our studies demonstrate that the activities of PKC alpha and PKC theta converge to regulate both IL-2 cytokine responses and T cell intrinsic alloreactivity in vivo. Mechanistically, this PKC alpha/theta crosstalk primarily affects the NFAT transactivation pathway in T lymphocytes, as observed by decreased phosphorylation of Ser-9 on GSK3 beta, reduced nuclear translocation and DNA binding of NFAT in isolated PKC alpha(-/-)/theta(-/-) CD3(+) T cells. This additive defect proved to be of physiological relevance, because PKC alpha(-/-)/theta(-/-) mice demonstrated significantly prolonged allograft survival in heart transplantation experiments, whereas both PKC alpha(-/-) and PKC theta(-/-) mice showed only minimal graft prolongation when compared to wild type controls. While PKC theta appears to be the rate-limiting PKC isotype mediating T lymphocyte activation, we here provide genetic evidence that PKC alpha and PKC theta have overlapping functions in alloimmunoreactivity in vivo and both PKC theta and PKC alpha isotypes must be targeted to prevent organ allograft rejection.
Gruber
Thomas
T
Department for Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Austria.
Hermann-Kleiter
Natascha
N
Pfeifhofer-Obermair
Christa
C
Lutz-Nicoladoni
Christina
C
Thuille
Nikolaus
N
Letschka
Thomas
T
Barsig
Johannes
J
Baudler
Monika
M
Li
Jianping
J
Metzler
Barbara
B
Nüsslein-Hildesheim
Barbara
B
Wagner
Juergen
J
Leitges
Michael
M
Baier
Gottfried
G
D019264:Adoptive Transfer; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D016923:Cell Death; D049109:Cell Proliferation; D004789:Enzyme Activation; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D016027:Heart Transplantation; D007376:Interleukin-2 / Q000378:metabolism; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism*; D016131:Lymphocyte Subsets / Q000201:enzymology; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D011493:Protein Kinase C / Q000172:deficiency / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000172:deficiency / Q000378:metabolism*; D000074121:Protein Kinase C-theta; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D015533:Transcriptional Activation; D014184:Transplantation, Homologous
D017252:CD3 Complex; D007376:Interleukin-2; D007527:Isoenzymes; D050778:NFATC Transcription Factors; D000071679:Glycogen Synthase Kinase 3 beta; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D000074121:Protein Kinase C-theta; D038362:Glycogen Synthase Kinase 3