Protein Kinase C Is Required for T Cell Activation and Homeostatic Proliferation

Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Science Signaling (Impact Factor: 6.28). 12/2011; 4(202):ra84. DOI: 10.1126/scisignal.2002058
Source: PubMed


Protein kinase C η (PKCη) is abundant in T cells and is recruited to the immunological synapse that is formed between a T cell and an antigen-presenting cell; however, its function in T cells is unknown. We showed that PKCη was required for the activation of mature CD8+ T cells through the T cell receptor. Compared with wild-type T cells, PKCη-/- T cells showed poor proliferation in response to antigen stimulation, a trait shared with T cells deficient in PKCθ, which is the most abundant PKC isoform in T cells and was thought to be the only PKC isoform with a specific role in T cell activation. In contrast, only PKCη-deficient T cells showed defective homeostatic proliferation, which requires self-antigen recognition. PKCη was dispensable for thymocyte development; however, thymocytes from mice doubly deficient in PKCη and PKCθ exhibited poor development, indicating some redundancy between the PKC isoforms. Deficiency in PKCη or PKCθ had opposing effects on the relative numbers of CD4+ and CD8+ T cells. PKCη-/- mice had a higher ratio of CD4+ to CD8+ T cells compared to that of wild-type mice, whereas PKCθ-/- mice had a lower ratio. Mice deficient in both isoforms exhibited normal cell ratios. Together, these data suggest that PKCη shares some redundant roles with PKCθ in T cell biology and also performs nonredundant functions that are required for T cell homeostasis and activation.

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Available from: Nicholas R J Gascoigne, Mar 12, 2014
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    • "It is generally thought that the C1 domains, which bind to the lipid second messenger diacylglycerol (DAG), play a central role in recruiting nPKCs to the IS. TCR engagement induces marked accumulation of DAG in the synaptic membrane, and studies suggest that the C1 domains of PKCθ, PKCε, and PKCη can recognize this DAG and respond accordingly [7], [9]–[11]. Nevertheless, there are indications that the C1 domains, on their own, are insufficient for sustained accumulation and subcompartmentalization within the IS, and that other elements within the nPKC structure, including the kinase domain and the C2 domain, are also critical for the process [12]–[14]. "
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    ABSTRACT: The immunological synapse (IS) formed between a T cell and its cognate antigen-presenting cell (APC) enables the directional secretion of cytolytic and inflammatory molecules. Synaptic architecture is established in part by a two-step cascade of novel protein kinase C (nPKC) isozymes. PKCε and PKCη arrive at the IS first, and occupy the entire synaptic membrane. Then, PKCθ accumulates in a smaller zone at the center of the contact. We investigated the molecular basis for this differential recruitment behavior using chimeric nPKC constructs and total internal reflection fluorescence microscopy. Our studies revealed that the V3 linker just N-terminal to the kinase domain plays a crucial role in specifying nPKC localization. Substitution of this linker switched the scope and the kinetics of PKCθ accumulation to that of PKCε and PKCη, and vice versa. Although the V3 was necessary for synaptic compartmentalization, it was not sufficient, as the tandem C1 domains were also required to mediate membrane association. Together, these results suggest a model whereby the V3 linker controls nPKC sub-compartmentalization after initial C1 domain-mediated accumulation at the IS.
    PLoS ONE 04/2014; 9(4):e95531. DOI:10.1371/journal.pone.0095531 · 3.23 Impact Factor
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    • "Recently, Fu et al. (2011) found a pivotal role of PKCη in T cell activation and homeostatic proliferation. Comparing the phenotypes of PKCη-/-, PKCθ-/-, and mice with a targeted disruption of both PKC isoforms, they were able to show that both isoforms share some redundancy in T cell biology. "
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    ABSTRACT: It is well established that members of the protein kinase C (PKC) family seem to have important roles in T cells. Focusing on the physiological and non-redundant PKC functions established in primary mouse T cells via germline gene-targeting approaches, our current knowledge defines two particularly critical PKC gene products, PKCθ and PKCα, as the "flavor of PKC" in T cells that appear to have a positive role in signaling pathways that are necessary for full antigen receptor-mediated T cell activation ex vivo and T cell-mediated immunity in vivo. Consistently, in spite of the current dogma that PKCθ inhibition might be sufficient to achieve complete immunosuppressive effects, more recent results have indicated that the pharmacological inhibition of PKCθ, and additionally, at least PKCα, appears to be needed to provide a successful approach for the prevention of allograft rejection and treatment of autoimmune diseases.
    Frontiers in Immunology 08/2012; 3:220. DOI:10.3389/fimmu.2012.00220
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    • "Positive selection of thymocytes in these double-knockout mice was more severely impaired than either single PKC-knockout mice. However, the blockade of thymocyte development in PKCη –/– θ –/– mice was not complete, as SP cell numbers were only reduced by about 50% (Figure 4A; Fu et al., 2011 "
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    ABSTRACT: Protein kinase Cη (PKCη) is a member of the novel PKC subfamily, which also includes δ, ε, and θ isoforms. Compared to the other novel PKCs, the function of PKCη in the immune system is largely unknown. Several studies have started to reveal the role of PKCη, particularly in T cells. PKCη is highly expressed in T cells, and is upregulated during thymocyte positive selection. Interestingly, like the θ isoform, PKCη is also recruited to the immunological synapse that is formed between a T cell and an antigen-presenting cell. However, unlike PKCθ, which becomes concentrated to the central region of the synapse, PKCη remains in a diffuse pattern over the whole area of the synapse, suggesting distinctive roles of these two isoforms in signal transduction. Although PKCη is dispensable for thymocyte development, further analysis of PKCη- or PKCθ-deficient and double-knockout mice revealed the redundancy of these two isoforms in thymocyte development. In contrast, PKCη rather than PKCθ, plays an important role for T cell homeostatic proliferation, which requires recognition of self-antigen. Another piece of evidence demonstrating that PKCη and PKCθ have isoform-specific as well as redundant roles come from the analysis of CD4 to CD8 T cell ratios in the periphery of these knockout mice. Deficiency in PKCη or PKCθ had opposing effects as PKCη knockout mice had a higher ratio of CD4 to CD8 T cells compared to that of wild-type mice, whereas PKCθ-deficient mice had a lower ratio. Biochemical studies showed that calcium flux and NFκB translocation is impaired in PKCη-deficient T cells upon TCR crosslinking stimulation, a character shared with PKCθ-deficient T cells. However, unlike the case with PKCθ, the mechanistic study of PKCη is at early stage and the signaling pathways involving PKCη, at least in T cells, are essentially unknown. In this review, we will cover the topics mentioned above as well as provide some perspectives for further investigations regarding PKCη.
    Frontiers in Immunology 06/2012; 3:177. DOI:10.3389/fimmu.2012.00177
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