Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases.
In the present study we have characterized T cell-driven immune function in mice that are genetically deficient in PKC theta. In response to simple immunologic stimulation invoked by in vivo T cell receptor (TCR) cross-linking, these mice showed significantly depressed plasma cytokine levels for IL-2, IL-4, IFNgamma, and TNFalpha compared to wild-type (WT) mice. In parallel, spleen mRNA levels for these cytokines were reduced, and NF-kappaB activation was also reduced in PKC theta knockouts (KO). Injection of allogeneic cells into the footpad of PKC theta deficient mice provoked a significantly diminished local T cell response compared to WT mice similarly challenged. Unlike comparable cells from wild type mice, CD45RBhi T cells harvested from PKC theta deficient mice failed to induce colitis in the SCID-CD45RB cell transfer model of IBD. In another T cell-dependent model of inflammatory disease, PKC theta deficient animals developed far less severe neurologic signs and reduced spinal cord inflammatory cell infiltrate compared to WT controls in the MOG-induced EAE model. A fundamental role for PKC theta in T cell activation and in the development of T cell-mediated inflammatory diseases is indicated by these results.
Anderson
Karen
K
Inflammation Department, Millennium Pharmaceuticals Inc., 40 Landsdowne St, Cambridge, MA 02139, USA. karen.anderson@novartis.com
Fitzgerald
Michael
M
Dupont
Michelle
M
Wang
Tao
T
Paz
Nancy
N
Dorsch
Marion
M
Healy
Aileen
A
Xu
Yajun
Y
Ocain
Tim
T
Schopf
Lisa
L
Jaffee
Bruce
B
Picarella
Dominic
D
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000473:pathology; D007527:Isoenzymes / Q000235:genetics* / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics* / Q000276:immunology; D000074121:Protein Kinase C-theta; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000378:metabolism
D015704:CD4 Antigens; D016207:Cytokines; D007527:Isoenzymes; D016328:NF-kappa B; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D017493:Leukocyte Common Antigens