Vitamin D Supplementation Modulates ICOS+ and ICOS− Regulatory T Cell in Siblings of Children With Type 1 Diabetes

Abstract

Objectives Vitamin D plays an immunoregulatory activity. The aim of this study was to assess the correlation between blood serum 25(OH)D levels and Th17 and Treg circulating subsets, mainly Treg/ICOS + which seems to have a protective role in autoimmunity, in children with T1D and their healthy siblings (S). The secondary aim was to evaluate the impact of vitamin D supplementation on these subsets. Patients and Methods 22 T1D and 33 S were enrolled. Glucose, HbA1c, 25(OH)D, Th17 (CD4 +CCR6 +), Treg (CD4 +CD25 +Foxp3 +), and Treg/ICOS + cells were evaluated. According to HLA haplotypes, subjects were classified as “at risk” (HLA +), "protective haplotypes" (HLA -; "nested controls"), and “undetermined” (HLA UND). T1D and S subjects were supplemented with cholecalciferol 1,000 IU/die and evaluated after 6 months. Results Vitamin D insufficiency (74.4 %) and deficiency (43%) were frequent. S subjects with 25(OH)D levels &25 nmol/L had Th17, Treg (p&0.01) and Treg/ICOS + (p&0.05) percentages higher than subjects with 25(OH)D >75 nmol/L. Treg/ICOS + percentages (p&0.05) were higher in HLA - S subjects compared to percentages observed in their siblings with T1D. At baseline, in S subjects, a decreasing trend in Th17 and Treg/ICOS + values (p&0.05) from vitamin D deficiency to sufficiency was observed; 25(OH)D levels were negative predictors of Treg/ICOS + (R-square: 0.301) and Th17 percentages (R-square: 0.138). After 6 months, supplemented S subjects showed higher 25(OH)D levels (p&0.0001), and lower Th17 (p&0.0001) and Treg/ICOS+ (p&0.05) percentages than at baseline; supplemented T1D patients only had a decrease in Th17 levels (p&0.05). Conclusion serum 25(OH)D levels seem to affect Th17 and Treg cell subsets in S subjects, consistent with its immunomodulating role. HLA role should be investigated in a larger population.

The role of CD4+FoxP3+ regulatory T cells in the immunopathogenesis of COVID-19: implications for treatment

“…Moreover, there is experimental and clinical evidence that high vitamin D levels are associated with an enhanced ratio of Treg/total T cells [110,111]. Oral administration of vitamin D3 can increase the absolute number of Tregs (CD4 + CD25 + FoxP3 + CD127 lo ) in the peripheral blood and enhance the immunosuppressive activity of Tregs in healthy adults and patients with autoimmune inflammatory diseases [111,112]. Therefore, vitamin D may have a beneficial effect in the management of SARS-CoV-2 infection by boosting Treg activity.…”

The Influence of Nutritional Factors on Immunological Outcomes

“…A positive effect of vitamin D on the augmentation of salivary immune responses was also found during stressful military training in healthy subjects, who showed higher salivary secretory immunoglobulin A and cathelicidin secretion rates (indices of mucosal immunity) after vitamin D supplementation ( 106 ). A possible therapeutic role of vitamin D in autoimmune diseases was highlighted in a study of patients with Hashimoto’s thyroiditis, in which vitamin D supplementation resulted in a significant reduction in anti-thyroglobulin antibodies ( 107 ), and in patients with type 1 diabetes, where vitamin D supplementation was shown to lower the levels of Th17 inflammatory cells ( 108 ). An anti-inflammatory effect of vitamin D was also found in patients with ulcerative colitis, who showed a significant decrease in serum proinflammatory cytokine levels (TNF-α, IFN-γ, and IL12p70) ( 109 ).…”

Vitamin D Repletion and AA/EPA Intake in Children with Type 1 Diabetes: Influences on Metabolic Status

“…Although the exact mechanism is still unclear, vitamin D metabolites have immune-modulating and anti-inflammatory actions, inhibiting T-cell activation and the modifying T-cell cytokine profile from a proinflammatory to an anti-inflammatory one [ 15 , 42 ]…”

“…Furthermore, also our group demonstrated a link between serum 25OHD levels, lymphocyte T helper 17 (Th17), and Treg with a costimulatory receptor (ICOS+) expressed on activated effector T cells in subjects with T1D and their siblings. Poor vitamin D levels in siblings cause a dysregulated immune response that can be partially improved by cholecalciferol therapy, suggesting a vitamin D role in phases before the beta cell destruction [ 15 ]. According to these and other findings, very recently, the Consensus Statements from the second and third International Conference on Controversies in Vitamin D underlined that increasing evidence suggests that vitamin D in autoimmune conditions, including T1D, could have a preventive rather than therapeutic role [ 16 , 17 ].…”