REGULATION OF IMMUNE RESPONSES Tolerogenic Dendritic Cells (tDC) Tolerogenic Dendritic cells (tDC), a particular dendritic cell subset, taking into account their ontogeny, occupy one of two central places in the system of antigen/allergen tolerance maintenance. The second place belongs to allergen-specific regulatory T (pTreg) cells. The main source of tDCs is immature DCs. The tDCs are induced by IL-2, IL-10, TGF-β, vitamin D3, retinoid acid, numerous immunosuppressive agents, which can represent cytokines such as IL-10, TGF-β, IL-27, endogenous immunosuppressants, such as glucocorticoids, vasoactive intestinal peptide (VIP), several synthetic immunosuppressive drugs (e.g., rapamycin, cyclosporine, aspirin), and natural products. Mechanisms of tDCs that provide tolerance include: (1) T-clonal deletion; (2) T-cell anergy; (3) promotion of pTregs proliferation; (4) inhibition of memory cells; (5) production of immunosuppressive cytokines; (6) secretion of enzymes inhibiting T cells; and (7) negative feedback regulation. In detail, tDCs produce immunosuppressive profile's cytokines, such as IL-10, TGF-β, IL-35, atypical neurotransmitter nitric oxide, and enzymes: IDO (indoleamine-2,3-dioxygenase) and HO-1 (heme oxygenase-1), which inhibit T-cell proliferation. IDO indirectly drives Treg differentiation by degradation of the essential amino acid tryptophan around effector T cells and concurrent production of toxic metabolites like kynurenines leading to apoptosis in T cells. The promotion of pTregs proliferation is described as a bidirectional coinfluence between tDCs and naïve T cells, leading to the main pTreg subset maturation. After that, pTregs turn on their tolerogenic activity suppressing helper T cells and Th-associated cytokines, promoting the expression of coinhibitory molecules, triggering apoptosis in effector T cells, producing the same immunosuppressive cytokines, and competing with proliferating lymphocytes for IL-2 by CD25+ molecule, a part of the IL-2 receptor. ©V.V.Klimov