PRKCQ

The role of PKC-θ in T cells

PKC-θ has a role in the transduction of signals in T cells, the kinase influences their activation, survival and growth. PKC-θ is important in the signal pathway integrating signals from TCR and CD28 receptors. A junction between an APC (an antigen presenting cell) and a T cell through their TCR and MHC receptors forms an immunological synapse. The active PKC-θ is localized in immunological synapse of T cells between the cSMAC (central supramolecular activation cluster containing TCR) and pSMAC (peripheral supramolecular activation cluster containing LFA-1 and ICAM-1). In regulatory T cells, PKC-θ is depleted from the region of immunological synapse, whereas in effector T cells, PKC-θ is present.^[6] As a result of co-stimulation by CD28 and TCR, PKC-θ is sumoylated by SUMO1 predominantly on the sites Lys325 and Lys506. Sumoylation is important because of forming of the immunological synapse.^[9] Subsequently, PKC-θ phosphorylates SPAK (STE20/SPS1-related, proline alanine-rich kinase) that activates the transcription factor AP-1 (activating protein-1). PKC-θ also initiates the assembly of proteins Carma-1, Bcl-10 and Malt-1 by phosphorylation of Carma-1. This complex of three proteins activates the transcription factor NF-κB (nuclear factor-κB). Furthermore, PKC-θ plays a role in the activation of transcription factor NF-AT (nuclear factor of activated T cells).^[10] Thus, PKC-θ promotes inflammation in effector T cells.^[6] PKC-θ plays a role in the activation of ILC2 and contribute to the proliferation of Th2 cells.^[11] The kinase PKC-θ is crucial for function of Th2 and Th17.^[6] Moreover, PKC-θ can translocate itself to the nucleus and by phosphorylation of histones increases the accessibility of transcriptional-memory-responsive genes in memory T cells.^[12] PKC-θ plays a role in anti-tumor activity of NK cells. It was observed that in mice without PKC-θ, MHCI-deficient tumors are more often.^[13]

The possible application of its inhibitors

Properties of PKC-θ make PKC-θ a good target for therapy in order to reduce harmful inflammation mediated by Th17 (mediating autoimmune diseases) or by Th2 (causing allergies)^[11] without diminishing the ability of T cells to get rid of viral-infected cells. Inhibitors could be used in T-cell mediated adaptive immune responses. Inhibition of PKC-θ downregulates transcription factors (NF-κB, NF-AT) and cause lower production of IL-2. It was observed that animals without PKC-θ are resistant to some autoimmune diseases.^[6] PKC-θ could be a target of inhibitors in the therapy of allergies.

The problem is that inhibitors of PKC-θ targeting catalytic sites may have toxic effects because of low specificity (catalytic sites among PKCs are very similar). Allosteric inhibitors have to be more specific to concrete isoforms of PKC.^[6] s.