Protein Kinase Cθ in T Cell Activation

Abstract

The novel protein kinase C (PKC) isoform, PKC theta, is selectively expressed in T lymphocytes and is a sine qua non for T cell antigen receptor (TCR)-triggered activation of mature T cells. Productive engagement of T cells by antigen-presenting cells (APCs) results in recruitment of PKC theta to the T cell-APC contact area--the immunological synapse--where it interacts with several signaling molecules to induce activation signals essential for productive T cell activation and IL-2 production. The transcription factors NF-kappa B and AP-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. PKC theta cooperates with the protein Ser/Thr phosphatase, calcineurin, in transducing signals leading to activation of JNK, NFAT, and the IL-2 gene. PKC theta also promotes T cell cycle progression and regulates programmed T cell death. The exact mode of regulation and immediate downstream substrates of PKC theta are still largely unknown. Identification of these molecules and determination of their mode of operation with respect to the function of PKC theta will provide essential information on the mechanism of T cell activation. 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.

Protein Kinase C-Theta Is Required for Development of Experimental Cerebral Malaria

“…8 PKC-is expressed in T cells and is a key component of T-cell receptor signaling and activation. 12,13,33,34 However, PKC--dependent pathways are differently required in T-cell activation and are especially critical for development of Th2 but not Th1 cells. 12,13 PKC-is not essential for T-cell activation leading to viral clearance.…”

T-Cell Receptor-Induced NF-κB Activation Is Negatively Regulated by E3 Ubiquitin Ligase Cbl-b

“…3C to E), suggests that Vav-1 functions as an adaptor protein to recruit PKC-to the cell membrane in proximity to p85, subsequently allowing it to be phosphorylated by PI3-K-dependent kinase(s). Although during T-cell activation, membrane-associated Vav-1-SLP-76 leads to PLC-␥ activation and production of diacylglycerol, which is important for PKC-activation (1,3,16), the loss of Cbl-b does not elicit elevated activation of PLC-␥1 or increased Ca 2ϩ influx in response to TCR stimulation (Fig. 1E) (2,4,25), arguing that Cbl-b may have a specific effect on Vav-1-mediated signaling events, independent of PLC-␥ activation.…”

“…Therefore, the data presented above indicate that Cbl-b negatively regulates the activation of both Akt and PKC-, two key molecules involved in TCR-and CD28-signaling pathways, leading to NF-B activation. Although PKC-is activated by diacylglycerol, a product of the cleavage of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) by phospholipase C␥1 (PLC-␥1) (1,3,16), the data generated from our laboratory and others indicate that the loss of Cbl-b does not affect PLC-␥1 activation and Ca 2ϩ influx (Fig. 1E) (2,4,18,25), suggesting that Cbl-b has a minimal effect on PLC-␥1-mediated activation of PKC-in T cells.…”

miR-146acontrols the resolution of T cell responses in mice

“…T cell activation is triggered by antigen engagement of the TCR, the sole molecule which determines the specificity of a T cell (Hannum et al, 1984). TCR engagement induces a signaling cascade leading to the activation of three major transcription factors: NFAT, AP-1, and NF-B (Isakov and Altman, 2002). Among them, NF-B plays a particularly important role and is involved in regulating almost all important aspects of T cell activation, including proliferation, survival, and effector functions (Schulze-Luehrmann and Ghosh, 2006).…”