Figure 4.

Mechanisms for adaptive immune responses to 1α,25(OH)₂D. Monocytes produce more LL-37 and β-defensin, enhance autophagy and NOD2 (nucleotide‑binding oligomerization domain‑containing protein 2) expression, decrease the production of inflammatory cytokines and downregulate TLR2/4 expression. Differentiation into macrophages is increased; the chemotactic and phagocytotic responses of macrophages and the production of antimicrobial proteins such as cathelicidin are upregulated. However, the stimulatory capacity of the antigen-presenting cells (APCs) and T cells is decreased. At the level of the APC, 1α,25(OH)₂D inhibits the differentiation into DCs, and thus stimulates effector CD4⁺ cells to differentiate into one of the four types of Th cells. Activated T cells also express VDR. 1α,25(OH)₂D inhibits the development of Th1 cells associated with the cellular immune response, and promotes Th2 cells associated with humoral (antibody) mediated immunity, thereby indirectly promoting the T cell shift from a Th1 towards a Th2 phenotype. 1α,25(OH)₂D also inhibits the development of Th17 cells, which play an essential role in combating certain pathogens and are linked to tissue damage and inflammation. Moreover, 1α,25(OH)₂D favors Treg cell development via modulating DCs and by directly targeting T cells. Finally, B cells are also affected by 1α,25(OH)₂D, demonstrating decreased immunoglobulin production, proliferation and differentiation, but increased apoptosis.