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Control of T cell activation by vitamin D

To the Editor:

We read with great interest the paper by von Essen et al. published in the April 2010 issue of Nature Immunology1. The authors show a critical difference in the expression of the T cell antigen receptor (TCR) pathway signaling molecule PLC-γ1 between naive CD4+ T cells and in vitro–primed CD4+ T cells. However, the suggested role of vitamin D in the induction of PLC-γ1 expression is disputable.

First, von Essen et al. demonstrate that expression of the vitamin D receptor (VDR) precedes PLC-γ1 expression after activation of freshly isolated CD4+ T cells and propose a causal relationship between these events. Such a relationship is unlikely, however, as neither the ligand of the VDR, 1,25-dihydroxyvitamin D (1,25(OH)2D3), nor its precursor, 25-hydroxyvitamin D (25(OH)D3), is reported to be present in the culture system.

Second, two normocalcemic analogs (ZK191784 and ZK203278) are erroneously used as VDR antagonists. Both analogs have been developed as therapeutic alternatives to 1,25(OH)2D3 because of their lack of effects on calcium homeostasis and their ability to retain the immunomodulatory potential of active vitamin D. Indeed, these molecules are comparable to 1,25(OH)2D3 in their ability to inhibit proliferation and cytokine production of peripheral blood mononuclear cells2,3. The claim that these compounds are VDR antagonists is based on a study with a structurally distinct analog (ZK159222), which indeed has antagonistic immunomodulatory effects4.

Third, the conclusions of the experiments using ketocanozole to block the hydroxylase CYP27B1 (which is required for intracellular conversion of the inactive vitamin D precursor 25(OH)D3 into 1,25 (OH)2D3) are premature. Ketoconazole is not a specific inhibitor of CYP27B1 and, moreover, inhibits the proliferation of T cells5. Additionally, 1,25(OH)2D3 and 25(OH)D3 are used in equal concentrations here, despite the over 100-fold greater potency of 1,25(OH)2D3 to inhibit the proliferation of CD4+ T cells6.

Finally, the lower T cell proliferation in vitamin D–deficient patients on chronic dialysis relative to that of healthy control subjects might be due to factors other than poor vitamin D status itself. In addition, the promotion of the proliferation of CD4+ T cells after exposure to 1,25(OH)2D3 is in contrast to numerous other published observations2,6,7.

In summary, von Essen et al. show that PLC-γ1 is upregulated after TCR triggering in a culture system in the presumed absence of 1,25(OH)2D3 and that the addition of VDR agonists inhibits T cell proliferation and PLC-γ1 expression. The conclusion that vitamin D stimulates the activation of human T cells by controlling the expression of VDR and PLC-γ1 is therefore questionable. Alternatively, as PLC-γ1 is expressed after T cell activation, the observed downregulation of PLC-γ1 in T cells exposed to VDR agonists can be explained by the inhibitory effects of 1,25(OH)2D3 on T cell activation.


  1. von Essen, M.R. et al. Nat. Immunol. 11, 344–349 (2010).

    CAS  Article  Google Scholar 

  2. Zugel, U. et al. J. Invest. Dermatol. 119, 1434–1442 (2002).

    CAS  Article  Google Scholar 

  3. Zugel, U. et al. Exp. Dermatol. 18, 619–627 (2009).

    Article  Google Scholar 

  4. Mizwicki, M.T. et al. J. Biol. Chem. 284, 36292–36301 (2009).

    CAS  Article  Google Scholar 

  5. Buttke, T.M. et al. Antimicrob. Agents Chemother. 24, 478–485 (1983).

    CAS  Article  Google Scholar 

  6. Correale, J. et al. Brain 132, 1146–1160 (2009).

    Article  Google Scholar 

  7. Jeffery, L.E. et al. J. Immunol. 183, 5458–5467 (2009).

    CAS  Article  Google Scholar 

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Correspondence to Joost Smolders.

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Smolders, J., Thewissen, M. & Damoiseaux, J. Control of T cell activation by vitamin D. Nat Immunol 12, 3 (2011).

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