Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial

Wakunyambo F  Maboshe; Helen M. MacDonald; Heather Wassall; William D. Fraser; Jonathan C Y  Tang; Shona Fielding; Robert N Barker; Mark A Vickers; Anthony Ormerod; Frank Thies

doi:10.3389/fimmu.2021.623087

Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial

Wakunyambo F Maboshe, Helen M. MacDonald, Heather Wassall, William D. Fraser, Jonathan C Y Tang, Shona Fielding, Robert N Barker, Mark A Vickers, Anthony Ormerod, Frank Thies^* (Corresponding Author)

^*Corresponding author for this work

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Abstract

Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown.

Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants.

Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed.

Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04).

Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation.

Original language	English
Article number	623087
Number of pages	12
Journal	Frontiers in Immunology
Volume	12
Early online date	28 Jun 2021
DOIs	https://doi.org/10.3389/fimmu.2021.623087
Publication status	Published - 28 Jun 2021

Bibliographical note

ACKNOWLEDGMENTS
We gratefully acknowledge all participants, the assistance of Karen Secombes for sample collection, Megan Forrester for advising on cytokine and flow cytometry analyses, and Rebecca Barr for packaging and blinding the supplement capsules. Vit D3 supplements were donated by Pure Encapsulations (Sudbury, MA).

FUNDING
Pathways to a healthy lifestyle studentship, RANK prize funding (WM), University of Aberdeen Development fund (HM), NHS endowments EA0702 (AO), Rural and Environment Science and Analytical Services Division of the Scottish government (RESAS) (FT). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 094847/Z/10/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

Keywords

Vitamin D
randomized control trial
T regulatory cells
interferon-gamma
seasonality
healthy subjects
immune markers

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© 2021 Maboshe, Macdonald, Wassall, Fraser, Tang, Fielding, Barker, Vickers, Ormerod and Thies. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. https://creativecommons.org/licenses/by/4.0/
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Maboshe, W. F., MacDonald, H. M., Wassall, H., Fraser, W. D., Tang, J. C. Y., Fielding, S., Barker, R. N., Vickers, M. A., Ormerod, A., & Thies, F. (2021). Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial. Frontiers in Immunology, 12, Article 623087. https://doi.org/10.3389/fimmu.2021.623087

Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial. / Maboshe, Wakunyambo F ; MacDonald, Helen M.; Wassall, Heather et al.
In: Frontiers in Immunology, Vol. 12, 623087, 28.06.2021.

Research output: Contribution to journal › Article › peer-review

Maboshe, WF, MacDonald, HM, Wassall, H, Fraser, WD, Tang, JCY, Fielding, S , Barker, RN , Vickers, MA , Ormerod, A & Thies, F 2021, 'Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial', Frontiers in Immunology, vol. 12, 623087. https://doi.org/10.3389/fimmu.2021.623087

Maboshe WF, MacDonald HM, Wassall H, Fraser WD, Tang JCY, Fielding S et al. Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial. Frontiers in Immunology. 2021 Jun 28;12:623087. Epub 2021 Jun 28. doi: 10.3389/fimmu.2021.623087

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title = "Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial",

abstract = "Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown.Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants.Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed.Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04).Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation.",

keywords = "Vitamin D, randomized control trial, T regulatory cells, interferon-gamma, seasonality, healthy subjects, immune markers",

author = "Maboshe, {Wakunyambo F} and MacDonald, {Helen M.} and Heather Wassall and Fraser, {William D.} and Tang, {Jonathan C Y} and Shona Fielding and Barker, {Robert N} and Vickers, {Mark A} and Anthony Ormerod and Frank Thies",

note = "ACKNOWLEDGMENTS We gratefully acknowledge all participants, the assistance of Karen Secombes for sample collection, Megan Forrester for advising on cytokine and flow cytometry analyses, and Rebecca Barr for packaging and blinding the supplement capsules. Vit D3 supplements were donated by Pure Encapsulations (Sudbury, MA). FUNDING Pathways to a healthy lifestyle studentship, RANK prize funding (WM), University of Aberdeen Development fund (HM), NHS endowments EA0702 (AO), Rural and Environment Science and Analytical Services Division of the Scottish government (RESAS) (FT). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 094847/Z/10/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. ",

year = "2021",

month = jun,

day = "28",

doi = "10.3389/fimmu.2021.623087",

language = "English",

volume = "12",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media S.A.",

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TY - JOUR

T1 - Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ

T2 - results from the D-SIRe2 randomised controlled trial

AU - Maboshe, Wakunyambo F

AU - MacDonald, Helen M.

AU - Wassall, Heather

AU - Fraser, William D.

AU - Tang, Jonathan C Y

AU - Fielding, Shona

AU - Barker, Robert N

AU - Vickers, Mark A

AU - Ormerod, Anthony

AU - Thies, Frank

N1 - ACKNOWLEDGMENTS We gratefully acknowledge all participants, the assistance of Karen Secombes for sample collection, Megan Forrester for advising on cytokine and flow cytometry analyses, and Rebecca Barr for packaging and blinding the supplement capsules. Vit D3 supplements were donated by Pure Encapsulations (Sudbury, MA). FUNDING Pathways to a healthy lifestyle studentship, RANK prize funding (WM), University of Aberdeen Development fund (HM), NHS endowments EA0702 (AO), Rural and Environment Science and Analytical Services Division of the Scottish government (RESAS) (FT). This research was funded in whole, or in part, by the Wellcome Trust [Grant number 094847/Z/10/Z]. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.

PY - 2021/6/28

Y1 - 2021/6/28

N2 - Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown.Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants.Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed.Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04).Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation.

AB - Background: Seasonal variations have been reported for immune markers. However, the relative contributions of sunlight and vitamin D variability on such seasonal changes are unknown.Objective: This double-blind, randomized, placebo-controlled trial tested whether daily 400 IU vitamin D3 supplementation affected short-term (12 weeks) and long-term (43 weeks) natural regulatory T cell (nTreg) populations in healthy participants.Design: 62 subjects were randomized equally to vitamin D versus placebo in March and assessed at baseline, April (4w), June (12w), September (25w) and January (43w). Circulating nTregs, ex vivo proliferation, IL-10 and IFN-γ productions were measured. Vitamin D metabolites and sunlight exposure were also assessed.Results: Mean serum 25-hydroxyvitamin D (25(OH)D) increased from 35.8(SD 3.0) to 65.3(2.6) nmol/L in April and remained above 75 nmol/L with vitamin D supplementation, whereas it increased from 36.4(3.2) to 49.8(3.5) nmol/L in June to fall back to 39.6(3.5) nmol/L in January with placebo. Immune markers varied similarly between groups according to the season, but independently of 25(OH)D. For nTregs, the mean (%CD3+CD4+CD127lo cells (SEM)) nadir observed in March (2.9(0.1)%) peaked in September at 4.0(0.2)%. Mean T cell proliferation peaked in June (33156(1813) CPM) returning to the nadir in January (17965(978) CPM), while IL-10 peaked in June and reached its nadir in September (median (IQR) of 262(283) to (121(194) pg/ml, respectively). Vitamin D attenuated the seasonal increase in IFN-γ by ~28% with mean ng/ml (SEM) for placebo vs vitamin D, respectively, for April 12.5(1.4) vs 10.0(1.2) (p=0.02); June 13.9(1.3) vs 10.2(1.7) (p=0.02) and January 7.4(1.1) vs 6.0(1.1) (p=0.04).Conclusions: Daily low dose Vitamin D intake did not affect the nTregs population. There were seasonal variation in nTregs, proliferative response and cytokines, suggesting that environmental changes influence immune response, but the mechanism seems independent of vitamin D status. Vitamin D attenuated the seasonal change in T cell-produced IFN-γ, suggesting a decrease in effector response which could be associated with inflammation.

KW - Vitamin D

KW - randomized control trial

KW - T regulatory cells

KW - interferon-gamma

KW - seasonality

KW - healthy subjects

KW - immune markers

U2 - 10.3389/fimmu.2021.623087

DO - 10.3389/fimmu.2021.623087

M3 - Article

C2 - 34262557

SN - 1664-3224

VL - 12

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 623087

ER -

Low-Dose Vitamin D3 Supplementation Does Not Affect Natural Regulatory T Cell Population but Attenuates Seasonal Changes in T Cell-Produced IFN-γ: results from the D-SIRe2 randomised controlled trial

Abstract

Bibliographical note

Keywords

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