Vitamin effects on the immune system: vitamins A and D take centre stage

Abstract

The metabolites of vitamins A and D, retinoic acid and 1,25(OH)₂VD₃, respectively, bind to nuclear receptors and exert potent and specific immunomodulatory effects. The vitamin D metabolite 1,25(OH)₂VD₃ inhibits T-helper 1 (T_H1)- and enhances T_H2-cell responses. It also decreases T_H17-cell differentiation, with reciprocal upregulation of forkhead box protein 3 (FOXP3)⁺ regulatory T (T_Reg) cells and T regulatory type 1 (T_R1) cells. 1,25(OH)₂VD₃ also inhibits the proliferation of B cells and their differentiation into antibody-secreting cells. Part of this effect might be indirect by decreasing T-cell help. 1,25(OH)₂VD₃ modulates dendritic cell (DC) function by impairing their maturation and enhancing their capacity to generate T_R1 cells. By contrast, 1,25(OH)₂VD₃ enhances the bactericidal capacity of macrophages. The vitamin A metabolite retinoic acid induces T_H2-cell responses. It also inhibits T_H17-cell differentiation and, reciprocally, potentiates T_Reg-cell development. Retinoic acid is synthesized by gut-associated DCs and induces the expression of gut-homing receptors α₄β₇-integrin and CC-chemokine receptor 9 (CCR9) by lymphocytes following activation. Conversely, retinoic acid blocks the upregulation of skin-homing receptors. Retinoic acid is also involved in the differentiation of IgA-secreting B cells in the gut. Given its potent immunomodulatory properties, 1,25(OH)₂VD₃ analogues are currently being tested in autoimmune diseases and as adjuvants for immunosuppressive therapy in transplantation.