Protein Kinase C θ Affects Ca2+ Mobilization and NFAT Activation in Primary Mouse T Cells

Pfeifhofer, Christa; Kofler, Kurt; Gruber, Thomas; Tabrizi, Nassim Ghaffari; Lutz, Christina; Maly, Karl; Leitges, Michael; Baier, Gottfried

doi:10.1084/jem.20020234

Cited by 313 publications

(447 citation statements)

References 46 publications

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“…Although there has been some controversy, available data suggest that PKCy is largely essential for activation of NF-kB via T-cell stimulation (Sun et al, 2000;Pfeifhofer et al, 2003) and can mediate the activation of IKK . PKCy is specifically recruited to the immunological synapse; although how PKCy but not other PKC isoforms is selectively recruited remains a mystery.…”

Section: Role Of Nf-jb In the Adaptive Responsementioning

confidence: 99%

NF-κB and the immune response

2006

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Section: Role Of Nf-jb In the Adaptive Responsementioning

confidence: 99%

NF-κB and the immune response

2006

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“…One of the early signaling cascades induced by the engagement of TCR at the IS is the tyrosine phosphorylation of phospholipase C-c, which hydrolyzes phosphatidylinositol 4,5 bisphosphate to inositol 1,4,5 trisphosphate (InsP 3 ) and diacylglycerol [6]. InsP 3 releases Ca 2+ from internal Ca 2+ stores and the Ca 2+ store depletion activates store-operated Ca 2+ channels called Ca 2+ release-activated Ca 2+ (CRAC)/ORAI channels in T cells [7,8].…”

Section: Introductionmentioning

confidence: 99%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse. Here we analyze the Ca 2+ dependence of proliferation and apoptosis in primary human CD4 + T cells following stimulation with anti-CD3/anti-CD28-coated beads, which induce a tight interaction similar to the immunological synapse. We found this focal stimulation to be much more efficient for stimulating IL-2 production and proliferation than non-focal TCR stimuli. Surprising little Ca 2+ entry through Ca 2+ channels was required for T cell proliferation. Transient free intracellular calcium concentration ([Ca 2+ ] i ) elevations of up to 220 nM from a baseline level of around 40 nM were sufficient for maximal proliferation in primary human CD4 + T cells. We also show that proliferation was very Ca 2+ sensitive in the range 90-120 nM, whereas apoptosis was basically constant for [Ca 2+ ] i levels of 90-120 nM. We conclude that very small changes in [Ca 2+ ] i can dramatically change the ratio between proliferation and apoptosis, thus keeping the balance between overshooting and inefficient immune responses.

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“…In cultured cell lines, PKC -mediated signal transduction has been shown to result in activation of the transcription factors, AP-1 and NF-B, in response to TCR/ CD28 costimulation, ultimately culminating in the induction of expression of genes that are essential for the proliferation and function of activated T cells (5)(6)(7)(8). The physiological functions of PKC for TCR signaling were subsequently demonstrated by two independent studies with PKC -deficient mice (9,10). Peripheral T cells of PKC Ϫ/Ϫ mice show reduced proliferation and IL-2 production and significant impairment in AP-1 and NF-B (9, 10) as well as NFAT (10) activation in response to TCR/CD28 stimulation.…”

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confidence: 97%

Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase Cθ-Deficient Mice

Tan

Zhao

et al. 2006

The Journal of Immunology

131

107

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The protein kinase Cθ (PKCθ) serine/threonine kinase has been implicated in signaling of T cell activation, proliferation, and cytokine production. However, the in vivo consequences of ablation of PKCθ on T cell function in inflammatory autoimmune disease have not been thoroughly examined. In this study we used PKCθ-deficient mice to investigate the potential involvement of PKCθ in the development of experimental autoimmune encephalomyelitis, a prototypic T cell-mediated autoimmune disease model of the CNS. We found that PKCθ−/− mice immunized with the myelin oligodendrocyte glycoprotein (MOG) peptide MOG35–55 were completely resistant to the development of clinical experimental autoimmune encephalomyelitis compared with wild-type control mice. Flow cytometric and histopathological analysis of the CNS revealed profound reduction of both T cell and macrophage infiltration and demyelination. Ex vivo MOG35–55 stimulation of splenic T lymphocytes from immunized PKCθ−/− mice revealed significantly reduced production of the Th1 cytokine IFN-γ as well as the T cell effector cytokine IL-17 despite comparable levels of IL-2 and IL-4 and similar cell proliferative responses. Furthermore, IL-17 expression was dramatically reduced in the CNS of PKCθ−/− mice compared with wild-type mice during the disease course. In addition, PKCθ−/− T cells failed to up-regulate LFA-1 expression in response to TCR activation, and LFA-1 expression was also significantly reduced in the spleens of MOG35–55-immunized PKCθ−/− mice as well as in in vitro-stimulated CD4+ T cells compared with wild-type mice. These results underscore the importance of PKCθ in the regulation of multiple T cell functions necessary for the development of autoimmune disease.

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Protein Kinase C θ Affects Ca2+ Mobilization and NFAT Activation in Primary Mouse T Cells

Cited by 313 publications

References 46 publications

NF-κB and the immune response

NF-κB and the immune response

Calcium dependence of T cell proliferation following focal stimulation

Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase Cθ-Deficient Mice

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