PKC-Theta Pathway
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PKC-Theta Pathway

An effective immune response depends on the ability of specialized immunocytes to identify foreign molecules and respond by differentiation into mature effector cells. A cell-surface antigen recognition apparatus and a complex intracellular receptor-coupled signal-transducing machinery mediate this tightly regulated process, which operate at high fidelity to discriminate self from nonself antigens. Activation of T-Cell requires sustained physical interaction of the TCR (T-Cell Receptor) with a MHC (Major Histocompatibility Complex)-presented peptide antigen that results in a temporal and spatial reorganization of multiple cellular elements at the T-Cell-Antigen Presenting Cell contact region, a specialized region referred to as the IS (Immunological Synapse) or Supramolecular Activation Cluster. Recent studies have identified PKC-Theta (Protein Kinase-C-Theta), a member of the Ca2+-independent PKC family, as an essential component of the T-Cell Supramolecular Activation Cluster that mediates several crucial functions in TCR-linked signaling leading to cell activation, differentiation, and survival through IL-2 gene induction (Ref.1).

The novel PKC isoform, PKC-Theta, is the only known member of the PKC family to assume center stage in the T-Cell Supramolecular Activation Cluster. High levels of PKC-Theta are expressed in skeletal muscle and lymphoid tissues, predominantly in the thymus and lymph nodes, with lower levels in spleen (Ref.2). T-Cell constitutes the primary location for PKC-Theta expression (Ref.3) and, among T-Cells, CD4+ and CD8+, single positive peripheral blood T-Cell and CD4+CD8+ double positive thymocytes, is found to express high levels of the protein. Productive engagement of T-Cell by Antigen Presenting Cells results in recruitment of PKC-Theta to the central zone of the Supramolecular Activation Cluster that brings it into close proximity with other effector molecules within the T-Cell signalosome, such as ZAP70 (Zeta-Associated Protein of 70 kDa), Lck and SLP76 (SH2 domain-containing Leukocyte Protein of 76 kDa), which mediate proximal activation events to convey activation signals to the IL-2 gene promoter, essential for productive T-Cell activation and IL-2 production. The IL-2 gene promoter includes consensus binding sites for multiple transcription factors, including Activator Protein-1 (a dimmer of c-Fos and c-Jun), NF-KappaB (Nuclear Factor-KappaB), NFAT (Nuclear Factor Of Activated T-Cells), and Oct1 (Octamer-Binding Protein-1); and cooperative interaction between these factors is required for efficient IL-2 induction (Ref.1). PKC-Theta cooperates with the protein Ser/Thr phosphatase, Calcineurin, in transducing signals leading to activation of JNK (c-Jun N-terminal Kinase), NFAT , and the IL-2 gene. PKC-Theta also promotes T-Cell cycle progression and regulates programmed T-Cell death.

TCR/CD3 engagement induces activation of Src (Fyn and Lck), Syk, ZAP70 and Tec-family PTKs, leading to stimulation and membrane recruitment of PLC-Gamma1 (Phospholipase-C-Gamma1), PI3K (Phosphatidylinositiol-3-Kinase) and Vav. Membrane recruitment of Vav is brought about via binding of SLP76 to the membrane protein LAT (Linker For Activation of T-Cells). A Vav-mediated pathway, which depends on Rac and Actin cytoskeleton reorganization as well as on PI3K, is responsible for the selective recruitment of PKC-Theta to the Supramolecular Activation Cluster. Vav is also essential for normal Ca2+ flux and NFAT activation (Ref.4). PLC-Gamma1-generated DAG (Diacylglycerol) plays a role for the initial recruitment of PKC-Theta. PLC-Gamma1-generated Ca2+ signals also activate Calcineurin via a pathway, which is relatively CD28/CTLA4 (Cytotoxic T-Lymphocyte Antigen-4)-independent. The receptor signals leading to activation of PKC-Theta and Calcineurin can be mimicked by phorbol ester PMA (Phorbol Myristate Acetate) and Ca2+ ionophore, respectively.

Upon TCR stimulation, PKC-Theta redistributes to the central Supramolecular Activation Cluster, where it transduces critical activation signals leading to IL-2 production and mount normal proliferative responses. The transcription factors NF-KappaB and Activator Protein-1 are the primary physiological targets of PKC-Theta, and efficient activation of these transcription factors by PKC-Theta requires integration of TCR and CD28 costimulatory signals. CD28 with its CD80/CD86 (B7-1/B7-2) ligands on Antigen Presenting Cells is required to localize PKC-Theta specifically to the Supramolecular Activation Cluster. The transcriptional element, which serves as a target for TCR/CD28 costimulation, is the CD28RE (CD28 Response Element) in the IL-2 promoter. CD28RE is a combinatorial binding site for NF-KappaB and Activator Protein-1. SEK1 (SAPK/ERK Kinase-1) and IKKs (I-KappaB Kinases) represent two important targets of PKC-Theta. Activation of Activator Protein-1 proceeds through the synergistic activation of JNK by SEK1 and Ca2+/Calcineurin signals (Ref.5). Positive regulation of Activator Protein-1 activation can also be achieved by PKC-Theta via another, JNK-independent pathway. Recent studies suggest that regulation of TCR coupling to NF-KappaB by PKC-Theta is effected through a variety of distinct mechanisms: PKC-Theta may directly associate with and regulate the IKK complex; or, PKC-Theta may regulate the IKK complex indirectly though CaMKII (Calcium/Calmodulin-Dependent Protein Kinase-II); or, it may act upstream of a newly described pathway involving a MAGUK (Membrane-Associated Guanylate Kinase Homolog), and the MALT-lymphoma-associated proteins: Bcl10 (B-Cell CLL/lymphoma-10) and MALT1 (Mucosa Associated Lymphoid Tissue Lymphoma Translocation Gene-1), which together regulate NF-KappaB and I-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells) via the IKK complex (Ref.3). The NFAT, Activator Protein-1 and CD28RE sites in the IL-2 promoter represent the critical targets for the action of PKC-Theta, thereby leading to induction of the IL-2 gene.

PKC-Theta has been found to promote AICD (Activation-induced T-Cell death), an important process that limits the expansion of activated antigen-specific T-Cells and ensures termination of an immune response once the specific pathogen has been cleared. Enzymatically active PKC-Theta selectively synergizes with Calcineurin to activate a caspase8-mediated Fas/FasL-dependent AICD. CD28 costimulation plays an essential role in TCR-mediated IL-2 production, and in its absence the T-Cell enters a stable state of unresponsiveness, termed anergy. PKC-Theta-mediated CREB (cAMP Responsive Element Binding Protein) phosphorylation and its subsequent binding to a cAMP-response element in the IL-2 promoter negatively regulate IL-2 transcription, thereby driving the responding T-Cells into an anergic state (Ref.1). The selective expression of PKC-Theta in T-Cells and its essential role in mature T-Cell activation establish it as an attractive drug target for immunosuppression in transplantation and autoimmune diseases. Thus, selective inhibition of PKC-Theta signaling can potentially abolish a T-Cell survival signal and thus promote the apoptosis of activated self-reactive T-Cells in autoimmune diseases and might be a useful strategy to interfere with several activation pathways and thereby modulate T-Cell costimulatory signals in inflammatory diseases (Ref.6).