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

TY - JOUR

T1 - The role of 1α,25-dihydroxyvitamin D3 and cytokines in the promotion of distinct Foxp3+ and IL-10+ CD4+ T cells

AU - Urry, Zoë

AU - Chambers, Emma S

AU - Xystrakis, Emmanuel

AU - Dimeloe, Sarah

AU - Richards, David F

AU - Gabryšová, Leona

AU - Christensen, Jillian

AU - Gupta, Atul

AU - Saglani, Sejal

AU - Bush, Andrew

AU - O'Garra, Anne

AU - Brown, Zarin

AU - Hawrylowicz, Catherine M

PY - 2012/10

Y1 - 2012/10

N2 - 1a,25-Dihydroxyvitamin D3 (1a25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1a25VitD3 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. 1a25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1a25VitD3 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 1a25VitD3 is impaired by IL-10. 1a25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3- T-cell counterparts. Equally, 1a25VitD3 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 1a25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1a25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.

AB - 1a,25-Dihydroxyvitamin D3 (1a25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1a25VitD3 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. 1a25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1a25VitD3 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 1a25VitD3 is impaired by IL-10. 1a25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3- T-cell counterparts. Equally, 1a25VitD3 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 1a25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1a25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.

KW - Animals

KW - Antigens, CD4

KW - Asthma

KW - Calcitriol

KW - Cells, Cultured

KW - Child

KW - Cytokines

KW - Forkhead Transcription Factors

KW - Humans

KW - Interleukin-10

KW - Lymphocyte Activation

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - T-Lymphocyte Subsets

KW - T-Lymphocytes, Regulatory

U2 - 10.1002/eji.201242370

DO - 10.1002/eji.201242370

M3 - Article

C2 - 22903229

SN - 0014-2980

VL - 42

SP - 2697

EP - 2708

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 10

ER -