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

Abstract

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.

PKC-θ selectively controls the adhesion-stimulating molecule Rap1

“…44,45 Mechanistically, the role of PKC-in immune responses is clearly established in mouse models of autoimmunity, asthma, and arthritis [46][47][48][49][50] ; nevertheless, the exact biochemical mechanisms of PKC-function(s) are enigmatic. Although several transcription factors essential for interleukin-2 (IL-2) induction (ie, nuclear factor B [NF-B], activator protein 1 [AP-1], and nuclear factor of activated T cells [NF-AT]) are regulated in part by PKC-, 44 additional physiologic and nonredundant functions of PKC-in T cells must be considered.…”

“…However, T lymphocytes express multiple isotypes of PKC, 29,44,[47][48][49][50] which are thought to exert substrate preferences through distinct subcellular localizations established via selective kinase/lipid and kinase/protein interactions. Recent studies have shown that at least 4 PKC isotypes are critical for T-cell activation.…”

“…PKC-has been shown to play an important role in IL-2 promoter transactivation as well as in T-cell immune responses in vivo. 32,45,[48][49][50]52 PKC-␣ is critical for interferon-␥ production and Th1 responses in vivo, 31 whereas PKC-␤ appears to function in LFA-1-mediated outside-in signaling leading to T-cell locomotion. 33 Furthermore, a significant, albeit partial, Th2 defect in PKC-KO mice indicated a biologic role of this atypical PKC isotype in T cell-dependent immune responses in vivo.…”

Protein Kinase C-θ Critically Regulates the Proliferation and Survival of Pathogen-Specific T Cells in Murine Listeriosis

“…The number of LM-and LCMV-specific CD4 and CD8 T cells was determined by an IFN-␥ specific ELISPOT as described previously (23 [33][34][35][36][37][38][39][40][41] (10 Ϫ8 M) peptide, respectively. Isolated splenic and hepatic leukocytes from infected BALB/c were coincubated with spleen cells from noninfected BALB/c WT mice (2 ϫ 10 5 /well), which were loaded with LLO 189 -200 (10 Ϫ6 M) or LLO 91-99 (10 Ϫ8 M) peptide.…”

ProtectiveToxoplasma gondii-Specific T-Cell Responses Require T-Cell-Specific Expression of Protein Kinase C-Theta

“…Functionally, PKC-is required for T-cell activation, proliferation, and survival (25,34,44). Experimental studies with mice have unequivocally demonstrated that PKC-is crucial for the activation of autoreactive T cells and induction of T-cell-mediated autoimmune diseases (2,16,36,48).…”