The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells

Eur J Immunol. 2012 Oct;42(10):2697-708. doi: 10.1002/eji.201242370. Epub 2012 Aug 20.

Abstract

1α,25-Dihydroxyvitamin D3 (1α25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1α25VitD3 promotes human and murine IL-10-secreting CD4(+) T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3(+) regulatory T (Treg) cells. 1α25VitD3 increased the frequency of both Foxp3(+) and IL-10(+) CD4(+) T cells in vitro. However, Foxp3 was increased at high concentrations of 1α25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3(+) and IL-10(+) T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1α25VitD3 is impaired by IL-10. 1α25VitD3 enables the selective expansion of Foxp3(+) Treg cells over their Foxp3(-) T-cell counterparts. Equally, 1α25VitD3 maintains Foxp3(+) expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4(+) Foxp3(+) T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1α25VitD3 enhances the frequency of both IL-10(+) and Foxp3(+) Treg cells. In a translational setting, these data suggest that 1α25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / immunology*
  • CD4 Antigens / metabolism
  • Calcitriol / pharmacology*
  • Cells, Cultured
  • Child
  • Cytokines / immunology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Humans
  • Interleukin-10 / metabolism*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology

Substances

  • CD4 Antigens
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-10
  • Calcitriol