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1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3

J Immunol. 2009 Nov 1;183(9):5458-67. doi: 10.4049/jimmunol.0803217.

Abstract

The active form of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), has potent immunomodulatory properties that have promoted its potential use in the prevention and treatment of infectious disease and autoimmune conditions. A variety of immune cells, including macrophages, dendritic cells, and activated T cells express the intracellular vitamin D receptor and are responsive to 1,25(OH)(2)D(3.) Despite this, how 1,25(OH)(2)D(3) regulates adaptive immunity remains unclear and may involve both direct and indirect effects on the proliferation and function of T cells. To further clarify this issue, we have assessed the effects of 1,25(OH)(2)D(3) on human CD4(+)CD25(-) T cells. We observed that stimulation of CD4(+)CD25(-) T cells in the presence of 1,25(OH)(2)D(3) inhibited production of proinflammatory cytokines including IFN- gamma, IL-17, and IL-21 but did not substantially affect T cell division. In contrast to its inhibitory effects on inflammatory cytokines, 1,25(OH)(2)D(3) stimulated expression of high levels of CTLA-4 as well as FoxP3, the latter requiring the presence of IL-2. T cells treated with 1,25(OH)(2)D(3) could suppress proliferation of normally responsive T cells, indicating that they possessed characteristics of adaptive regulatory T cells. Our results suggest that 1,25(OH)(2)D(3) and IL-2 have direct synergistic effects on activated T cells, acting as potent anti-inflammatory agents and physiologic inducers of adaptive regulatory T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antigens, CD / biosynthesis*
  • CTLA-4 Antigen
  • Calcitriol / pharmacology*
  • Cell Differentiation / immunology*
  • Cell Proliferation / drug effects
  • Cytokines / antagonists & inhibitors*
  • Cytokines / biosynthesis
  • Drug Combinations
  • Forkhead Transcription Factors / biosynthesis*
  • Humans
  • Inflammation Mediators / antagonists & inhibitors*
  • Inflammation Mediators / metabolism
  • Interleukin-2 / physiology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Antigens, CD
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cytokines
  • Drug Combinations
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Inflammation Mediators
  • Interleukin-2
  • Calcitriol