Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Peled, J.U. et al. The biochemistry of somatic hypermutation. Annu. Rev. Immunol. 26, 481–511 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Margulies, D.H. TCR avidity: it's not how strong you make it, it's how you make it strong. Nat. Immunol. 2, 669–670 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Slifka, M.K. & Whitton, J.L. Functional avidity maturation of CD8+ T cells without selection of higher affinity TCR. Nat. Immunol. 2, 711–717 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Akbar, A.N., Terry, L., Timms, A., Beverley, P.C. & Janossy, G. Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J. Immunol. 140, 2171–2178 (1988).

    CAS  PubMed  Google Scholar 

  5. Byrne, J.A., Butler, J.L. & Cooper, M.D. Differential activation requirements for virgin and memory T cells. J. Immunol. 141, 3249–3257 (1988).

    CAS  PubMed  Google Scholar 

  6. Sanders, M.E., Makgoba, M.W., June, C.H., Young, H.A. & Shaw, S. Enhanced responsiveness of human memory T cells to CD2 and CD3 receptor-mediated activation. Eur. J. Immunol. 19, 803–808 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Luqman, M. & Bottomly, K. Activation requirements for CD4+ T cells differing in CD45R expression. J. Immunol. 149, 2300–2306 (1992).

    CAS  PubMed  Google Scholar 

  9. Sagerstrom, C.G., Kerr, E.M., Allison, J.P. & Davis, M.M. Activation and differentiation requirements of primary T cells in vitro. Proc. Natl. Acad. Sci. USA 90, 8987–8991 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Croft, M., Bradley, L.M. & Swain, S.L. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J. Immunol. 152, 2675–2685 (1994).

    CAS  PubMed  Google Scholar 

  11. Pihlgren, M., Dubois, P.M., Tomkowiak, M., Sjogren, T. & Marvel, J. Resting memory CD8+ T cells are hyperreactive to antigenic challenge in vitro. J. Exp. Med. 184, 2141–2151 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Curtsinger, J.M., Lins, D.C. & Mescher, M.F. CD8+ memory T cells (CD44high, Ly-6C+) are more sensitive than naive cells to (CD44low, Ly-6C) to TCR/CD8 signaling in response to antigen. J. Immunol. 160, 3236–3243 (1998).

    CAS  PubMed  Google Scholar 

  13. Robinson, A.T., Miller, N. & Alexander, D.R. CD3 antigen-mediated calcium signals and protein kinase C activation are higher in CD45R0+ than in CD45RA+ human T lymphocyte subsets. Eur. J. Immunol. 23, 61–68 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Ericsson, P.O., Orchansky, P.L., Carlow, D.A. & Teh, H.S. Differential activation of phospholipase C-γ1 and mitogen-activated protein kinase in naive and antigen-primed CD4 T cells by the peptide/MHC ligand. J. Immunol. 156, 2045–2053 (1996).

    CAS  PubMed  Google Scholar 

  15. Abraham, R.T. & Weiss, A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nat. Rev. Immunol. 4, 301–308 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Smith-Garvin, J.E., Koretzky, G.A. & Jordan, M.S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Salvador, J.M. et al. Alternative p38 activation pathway mediated by T cell receptor-proximal tyrosine kinases. Nat. Immunol. 6, 390–395 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Ashwell, J.D. The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat. Rev. Immunol. 6, 532–540 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Finco, T.S., Kadlecek, T., Zhang, W., Samelson, L.E. & Weiss, A. LAT is required for TCR-mediated activation of PLCγ1 and the Ras pathway. Immunity 9, 617–626 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Mittelstadt, P.R., Yamaguchi, H., Appella, E. & Ashwell, J.D. T cell receptor-mediated activation of p38α by mono-phosphorylation of the activation loop results in altered substrate specificity. J. Biol. Chem. 284, 15469–15474 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lauritsen, J.P.H. et al. Two distinct pathways exist for down-regulation of the TCR. J. Immunol. 161, 260–267 (1998).

    CAS  PubMed  Google Scholar 

  22. Chakrabarti, R., Jung, C.Y., Lee, T.P., Liu, H. & Mookerjee, B.K. Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. J. Immunol. 152, 2660–2668 (1994).

    CAS  PubMed  Google Scholar 

  23. Pillai, S., Bikle, D.D., Su, M.J., Ratnam, A. & Abe, J. 1,25-Dihydroxyvitamin D3 upregulates the phosphatidylinositol signaling pathway in human keratinocytes by increasing phospholipase C levels. J. Clin. Invest. 96, 602–609 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Xie, Z. & Bikle, D.D. Cloning of the human phospholipase C-gamma1 promoter and identification of a DR6-type vitamin D-responsive element. J. Biol. Chem. 272, 6573–6577 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Provvedini, D.M., Tsoukas, C.D., Deftos, L.J. & Manolagas, S.C. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 221, 1181–1183 (1983).

    Article  CAS  PubMed  Google Scholar 

  26. Mizwicki, M.T., Bula, C.M., Bishop, J.E. & Norman, A.W. New insights into vitamin D sterol-VDR proteolysis, allostery, structure-function from the perspective of a conformational ensemble model. J. Steroid Biochem. Mol. Biol. 103, 243–262 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zugel, U., Steinmeyer, A., Giesen, C. & Asadullah, K. A novel immunosuppressive 1α,25-dihydroxyvitamin D3 analog with reduced hypercalcemic activity. J. Invest. Dermatol. 119, 1434–1442 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Zugel, U., Steinmeyer, A., May, E., Lehmann, M. & Asadullah, K. Immunomodulation by a novel, dissociated Vitamin D analogue. Exp. Dermatol. 18, 619–627 (2009).

    Article  PubMed  Google Scholar 

  29. Mizwicki, M.T. et al. On the mechanism underlying (23S)-25-dehydro-1α(OH)-vitamin D3–26,23-lactone antagonism of hVDRwt gene activation and its switch to a superagonist. J. Biol. Chem. 284, 36292–36301 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Neufeld, T.P. & Edgar, B.A. Connections between growth and the cell cycle. Curr. Opin. Cell Biol. 10, 784–790 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Liu, P.T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Costa, E.M. & Feldman, D. Measurement of 1,25-dihydroxyvitamin D3 receptor turnover by dense amino acid labeling: changes during receptor up-regulation by vitamin D metabolites. Endocrinology 120, 1173–1178 (1987).

    Article  CAS  PubMed  Google Scholar 

  34. Qi, X. et al. The p38 and JNK pathways cooperate to trans-activate vitamin D receptor via c-Jun/AP-1 and sensitize human breast cancer cells to vitamin D3-induced growth inhibition. J. Biol. Chem. 277, 25884–25892 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Maiti, A., Hait, N.C. & Beckman, M.J. Extracellular calcium-sensing receptor activation induces vitamin D receptor levels in proximal kidney HK-2G cells by a mechanism that requires phosphorylation of p38α MAPK. J. Biol. Chem. 283, 175–183 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Irvin, B.J., Williams, B.L., Nilson, A.E., Maynor, H.O. & Abraham, R.T. Pleiotropic contributions of phospholipase C-γ1 (PLC-γ1) to T-cell antigen receptor-mediated signaling: reconstitution studies of a PLC-γ1-deficient Jurkat T-cell line. Mol. Cell. Biol. 20, 9149–9161 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Harden, T.K. & Sondek, J. Regulation of phospholipase C isozymes by Ras superfamily GTPases. Annu. Rev. Pharmacol. Toxicol. 46, 355–379 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Ting, A.T., Karnitz, L.M., Schoon, R.A., Abraham, R.T. & Leibson, P.J. Fc gamma receptor activation induces the tyrosine phosphorylation of both phospholipase C (PLC)-γ1 and PLC-γ2 in natural killer cells. J. Exp. Med. 176, 1751–1755 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Dienz, O. et al. Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and phospholipase Cγ1 are required for NF-kappa B activation and lipid raft recruitment of protein kinase Cθ induced by T cell costimulation. J. Immunol. 170, 365–372 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Veldman, C.M., Cantorna, M.T. & DeLuca, H.F. Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system. Arch. Biochem. Biophys. 374, 334–338 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Yu, S. & Cantorna, M.T. The vitamin D receptor is required for iNKT cell development. Proc. Natl. Acad. Sci. USA 105, 5207–5212 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yu, S., Bruce, D., Froicu, M., Weaver, V. & Cantorna, M.T. Failure of T cell homing, reduced CD4/CD8αα intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice. Proc. Natl. Acad. Sci. USA 105, 20834–20839 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Mathieu, C. et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J. Bone Miner. Res. 16, 2057–2065 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Dong, S. et al. T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J. Exp. Med. 203, 2509–2518 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang, W., Irvin, B.J., Trible, R.P., Abraham, R.T. & Samelson, L.E. Functional analysis of LAT in TCR-mediated signaling pathways using a LAT-deficient Jurkat cell line. Int. Immunol. 11, 943–950 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Lin, J., Weiss, A. & Finco, T.S. Localization of LAT in glycolipid-enriched microdomains is required for T cell activation. J. Biol. Chem. 274, 28861–28864 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Whitmire, J.K., Eam, B. & Whitton, J.L. Tentative T cells: memory cells are quick to respond, but slow to divide. PLoS Pathog. 4, e1000041 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Geisler, C. et al. Characterization and expression of the human T cell receptor-T3 complex by monoclonal antibody F101.01. Scand. J. Immunol. 27, 685–696 (1988).

    Article  CAS  PubMed  Google Scholar 

  49. Kadi, F. et al. The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J. Physiol. (Lond.) 558, 1005–1012 (2004).

    Article  CAS  Google Scholar 

  50. Bonefeld, C.M. et al. TCR down-regulation controls virus-specific CD8+ T cell responses. J. Immunol. 181, 7786–7799 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Carsten Geisler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1851

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing