The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells.
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.
MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK.
Zoë
Z
Urry
Emma S
ES
Chambers
Emmanuel
E
Xystrakis
Sarah
S
Dimeloe
David F
DF
Richards
Leona
L
Gabryšová
Jillian
J
Christensen
Atul
A
Gupta
Sejal
S
Saglani
Andrew
A
Bush
Anne
A
O'Garra
Zarin
Z
Brown
Catherine M
CM
Hawrylowicz
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
D015704:CD4 Antigens; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016753:Interleukin-10; D002117:Calcitriol