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

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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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 languageEnglish
Article number623087
Number of pages12
JournalFrontiers in Immunology
Early online date28 Jun 2021
Publication statusPublished - 28 Jun 2021

Bibliographical note

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).

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.


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


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