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Vitamin D controls T cell antigen receptor signaling and activation of human T cells

Abstract

Phospholipase C (PLC) isozymes are key signaling proteins downstream of many extracellular stimuli. Here we show that naive human T cells had very low expression of PLC-γ1 and that this correlated with low T cell antigen receptor (TCR) responsiveness in naive T cells. However, TCR triggering led to an upregulation of 75-fold in PLC-γ1 expression, which correlated with greater TCR responsiveness. Induction of PLC-γ1 was dependent on vitamin D and expression of the vitamin D receptor (VDR). Naive T cells did not express VDR, but VDR expression was induced by TCR signaling via the alternative mitogen-activated protein kinase p38 pathway. Thus, initial TCR signaling via p38 leads to successive induction of VDR and PLC-γ1, which are required for subsequent classical TCR signaling and T cell activation.

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Figure 1: Lower sensitivity of naive T cells to TCR triggering.
Figure 2: Phosphorylation and expression of PLC-γ1 in naive and primed T cells.
Figure 3: VDR induction precedes PLC-γ1 upregulation.
Figure 4: The alternative TCR signaling pathway induces VDR expression.

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Acknowledgements

We thank Bayer Schering Pharma AG for the VDR antagonists ZK191784 and ZK203278. Supported by The Danish Medical Research Council, The Lundbeck Foundation, The Novo Nordisk Foundation, The King Christian the 10th Foundation and The A.P. Møller Foundation for the Advancement of Medical Sciences.

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M.R.v.E. did most of the experiments, analyzed data and contributed to the writing of the manuscript; M.K. and P.S. contributed to the ketoconazole and mRNA experiments; K.O. contributed to the planning and analyses of studies involving patients; N.Ø. contributed to the design and analysis of some of the experiments; and C.G. conceptualized the research, directed the study, analyzed data and wrote the manuscript.

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Correspondence to Carsten Geisler.

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von Essen, M., Kongsbak, M., Schjerling, P. et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 11, 344–349 (2010). https://doi.org/10.1038/ni.1851

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