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PKC theta cooperates with PKC alpha in alloimmune responses of T cells in vivo.
- Source :
-
Molecular immunology [Mol Immunol] 2009 Jun; Vol. 46 (10), pp. 2071-9. Date of Electronic Publication: 2009 Apr 07. - Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Adoptive Transfer
Animals
CD3 Complex metabolism
Cell Death
Cell Proliferation
Enzyme Activation
Flow Cytometry
Glycogen Synthase Kinase 3 metabolism
Glycogen Synthase Kinase 3 beta
Heart Transplantation
Interleukin-2 metabolism
Isoenzymes deficiency
Lymphocyte Subsets enzymology
Mice
NFATC Transcription Factors metabolism
Protein Kinase C deficiency
Protein Kinase C-alpha deficiency
Protein Kinase C-theta
T-Lymphocytes cytology
Transcriptional Activation
Transplantation, Homologous
Isoenzymes metabolism
Protein Kinase C metabolism
Protein Kinase C-alpha metabolism
T-Lymphocytes enzymology
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9142
- Volume :
- 46
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular immunology
- Publication Type :
- Academic Journal
- Accession number :
- 19356803
- Full Text :
- https://doi.org/10.1016/j.molimm.2009.02.030