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.
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.
Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham Medical School, Birmingham, United Kingdom.
Louisa E
LE
Jeffery
Fiona
F
Burke
Manuela
M
Mura
Yong
Y
Zheng
Omar S
OS
Qureshi
Martin
M
Hewison
Lucy S K
LS
Walker
David A
DA
Lammas
Karim
K
Raza
David M
DM
Sansom
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015703:Antigens, CD / Q000096:biosynthesis*; D060908:CTLA-4 Antigen; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004338:Drug Combinations; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007376:Interleukin-2 / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D004338:Drug Combinations; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D018836:Inflammation Mediators; D007376:Interleukin-2; D002117:Calcitriol