Abstract
Protein kinase C (PKC)-θ is the only member of the PKC family that has the ability to translocate to the immunological synapse between T cells and antigen-presenting cells upon T cell receptor and MHC-II recognition. PKC-θ interacts functionally and physically with other downstream effector molecules to mediate T cell activation, differentiation, and migration. It plays a critical role in the generation of Th2 and Th17 responses and is less important in Th1 and CTL responses. PKC-θ has been recently shown to play a role in the nucleus, where it mediates inducible gene expression in the development of memory CD4+ T cells. This novel PKC (nPKC) can up-regulate HIV-1 transcription and PKC-θ activators such as Prostratin have been used in early HIV-1 reservoir eradication studies. The exact manner of the activation of virus by these compounds and the role of PKC-θ, particularly its nuclear form and its association with NF-κB in both the cytoplasmic and nuclear compartments, needs further precise elucidation especially given the very important role of NF-κB in regulating transcription from the integrated retrovirus. Continued studies of this nPKC isoform will give further insight into the complexity of T cell signaling kinases.
Highlights
CD4+ T cells play a central role in the function of the immune system; they help B cells to produce antibodies, they can orchestrate CD8+ T cells and macrophages against a wide variety of pathogens, and CD4+ T cells can become cytotoxic cells that are capable of direct cell killing [1,2,3,4]
Ca2+ and phorbol ester tumor promoters [e.g., phorbol myristate acetate (PMA)] were able to mimic the T cell receptor (TCR) and coreceptor signals that lead to full T cell activation, resulting in IL-2 production and proliferation [14, 15], which are important for the elicitation of rapid T cell responses in vitro
While in vitro experiments may give some insight to outcomes, it is likely that in vivo experiments in models, such as humanized mice, will be required to dissect these effects. These findings demonstrate that Protein kinase C (PKC)-θ may play an important role in HIV-1 pathogenesis, and its role in the nucleus in the context modulating HIV transcription requires further investigation
Summary
CD4+ T cells play a central role in the function of the immune system; they help B cells to produce antibodies, they can orchestrate CD8+ T cells and macrophages against a wide variety of pathogens, and CD4+ T cells can become cytotoxic cells that are capable of direct cell killing [1,2,3,4]. Studies revealed that TCR engagement led to phospholipase C-γ1 (PLC γ1)-mediated hydrolysis of membrane inositol phospholipids that resulted in the subsequent production of inositol phosphate and diacylglycerol (DAG) These lipid esters were found to increase intracellular calcium (Ca2+) concentrations and activate certain protein kinase C (PKC) isoforms [13]. Ca2+ and phorbol ester tumor promoters [e.g., phorbol myristate acetate (PMA)] were able to mimic the TCR and coreceptor signals that lead to full T cell activation, resulting in IL-2 production and proliferation [14, 15], which are important for the elicitation of rapid T cell responses in vitro. This review will focus on the importance of protein complexes that involve kinases (PKCs) in CD4+ T cells; particular emphasis will be placed on the role of PKC-θ in the IS and its newly discovered role within the nucleus
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