Mice deficient in PKC theta demonstrate impaired in vivo T cell activation and protection from T cell-mediated inflammatory diseases

• Published in: Autoimmunity (Chur, Switzerland) Switzerland), 2006-09, Vol.39 (6), p.469-478
• Main Authors: Anderson, Karen, Fitzgerald, Michael, DuPont, Michelle, Wang, Tao, Paz, Nancy, Dorsch, Marion, Healy, Aileen, Xu, Yajun, Ocain, Tim, Schopf, Lisa, Jaffee, Bruce, Picarella, Dominic
• Format: Article
• Language: English
• Subjects: Animals; autoimmune disease; Biological and medical sciences; CD4 Antigens - immunology; Cell Proliferation; Cytokines - blood; Cytokines - metabolism; Disease Models, Animal; EAE; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Enzyme Activation; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; General aspects; IBD; Immunopathology; Inflammation - immunology; Inflammation - pathology; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - pathology; Isoenzymes - genetics; Isoenzymes - immunology; Leukocyte Common Antigens - immunology; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocyte Activation; Medical sciences; Mice; Mice, Knockout; Mice, SCID; NF-kappa B - metabolism; PKC theta; Protein Kinase C - genetics; Protein Kinase C - immunology; Protein Kinase C-theta; Receptors, Antigen, T-Cell - immunology; RNA, Messenger - blood; RNA, Messenger - metabolism; Spinal Cord - immunology; Spinal Cord - pathology; Spleen - metabolism; T cell activation
• ISSN: 0891-6934; 1607-842X
• DOI: 10.1080/08916930600907954

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, IFNγ, and TNFα compared to wild-type (WT) mice. In parallel, spleen mRNA levels for these cytokines were reduced, and NF-κB 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.