Vitamin A and retinoic acid in T cell-related immunity

Abstract

Interest in vitamin A as a regulator of immune function goes back to the early 1900s. Recently, several lines of evidence have converged to show that retinoic acid (RA), a major oxidative metabolite of vitamin A, plays a key role in the differentiation of T cell subsets, the migration of T cells into tissues, and the proper development of T cell-dependent antibody responses. This review discusses evidence from experimental studies that RA promotes the differentiation of regulatory T cells, which help to suppress inflammatory reactions, and plays a significant role in normal mucosal immunity by modulating T cell activation and regulating cell trafficking. RA also promotes antibody responses to T cell-dependent antigens. Conversely, in a state of vitamin A deficiency, inflammatory T cell reactions may be inadequately opposed and therefore become dominant. Although data from human studies are still needed, the framework now developed from studies in mice and rat models suggests that adequate vitamin A status, whether derived from ingestion of preformed retinol or β-carotene, is important for maintaining a proper balance of well-regulated T cell functions and for preventing excessive or prolonged inflammatory reactions.

FIGURE 1.

Model of T cell differentiation, after contact with antigen-activated DCs, from uncommitted naive T cells into different T cell subsets that produce different cytokines and thus promote different functional activities. Black arrows indicate the cytokines that mainly drive the differentiation to specific subsets. RA together with TGF-β promotes the differentiation of Treg cells, which generally are antiinflammatory, whereas RA also decreases Th1 activity and often promotes Th2 functions (see text). Upward arrows show proposed “plasticity” or interconversion among some of the T cell subsets (see references , , and for detailed reviews). The signature cytokines and potential outcomes, which also are determined by the environment and type of pathogen or antigen encountered, are listed. Effects of vitamin A or RA differ contextually but generally limit Th1 and Th17 processes while increasing Th2 and Treg-mediated processes. Ab, antibody; DC, dendritic cells; Fox, forkhead; IFNγ, interferon γ; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; RA, retinoic acid; RORγt, retinoid orphan receptor γt; TGFβ, transforming growth factor β; Th, T helper; Treg, T-regulatory.