Regulatory Multitasking of Tolerogenic Dendritic Cells – Lessons Taken from Vitamin D3-Treated Tolerogenic Dendritic Cells

Abstract

Tolerogenic dendritic cells (DCs) work through silencing of differentiated antigen-specific T cells, activation and expansion of naturally occurring T regulatory cells (Tregs), transfer of regulatory properties to T cells, and the differentiation of naïve T cells into Tregs. Due to an operational definition based on T cell activation assays, the identity of tolerogenic DCs has been a matter of debate and it need not represent a specialized DC subset. Human tolerogenic DCs generated in vitro using inhibitory cytokines, growth factors, natural immunomodulators, or genetic manipulation have been effective and several of these tolerogenic DCs are currently being tested for clinical use. Ex vivo generated tolerogenic DCs reduce activation of naïve T cells using various means, promote a variety of regulatory T cells and most importantly, frequently show stable inhibitory phenotypes upon repetitive maturation with inflammatory factors. Yet, tolerogenic DCs differ with respect to the phenotype or the number of regulatory mechanisms they employ to modulate the immune system. In our experience, tolerogenic DCs generated using the biologically active form of vitamin D (VD3-DCs), alone, or combined with dexamethasone are proficient in their immunoregulatory functions. These tolerogenic DCs show a stable maturation-resistant semi-mature phenotype with low expression of activating co-stimulatory molecules, no production of the IL-12 family of cytokines and high expression of inhibitory molecules and IL-10. VD3-DCs induce increased apoptosis of effector T cells and induce antigen-specific regulatory T cells, which work through linked suppression ensuring infectious tolerance. Lessons learned on VD3-DCs help understanding the contribution of different pattern-recognition receptors (PRRs) and secondary signals to the tolerogenic function and how a cross-talk between DCs and T cells translates into immune regulation.

Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

“…This gives Correspondence: Dr. Mahdad Noursadeghi e-mail: m.noursadeghi@ucl.ac.uk way to the potential for vitamin D supplementation [1][2][3][4] or ex vivo conditioning of DCs with vitamin D for cell therapy strategies [5]. Vitamin D is synthesized from 7-dehydrocholesterol in the skin following exposure to ultraviolet B radiation and thermal isomerisation, or replenished by dietary intake.…”

Vitamin D immunoregulation through dendritic cells

“…This concept, extensively reviewed,3, 5, 12, 13, 14, 15, 16, 17, 18 arose from studies of GM‐CSF‐driven differentiation of human blood CD14 + monocytes into motile cells with dendrites (moDC), capable of presenting antigen on MHC class II (MHCII) 19. The properties of these in‐vitro ‐generated moDC were substantially altered when 1,25‐OH‐VD3 was included during their differentiation: VD3‐‘tolerized’ moDC were less effective in their induction of T‐cell proliferation,20 but rather induced Treg cells that promoted transplant tolerance 21, 22.…”

“…The properties of these in‐vitro ‐generated moDC were substantially altered when 1,25‐OH‐VD3 was included during their differentiation: VD3‐‘tolerized’ moDC were less effective in their induction of T‐cell proliferation,20 but rather induced Treg cells that promoted transplant tolerance 21, 22. MoDC generated in the presence of 1,25‐OH‐VD3 were less capable of producing interleukin‐12 (IL‐12) p70,23 but rather secreted IL‐10 14, 24. These cells also possess decreased densities of the co‐stimulatory molecules CD80 and CD86 and of the antigen‐presenting MHCII complex 20, 23.…”

MECHANISMS IN ENDOCRINOLOGY: Vitamin D as a potential contributor in endocrine health and disease

“…In NOD mice, such analogs can prevent the progression of the disease (24,25), which has been postulated to be due to the direct b-cell protective effects of 1,25(OH) 2 D combined with the blocking of inflammation, together with the regulator T lymphocytes, which may be partly a direct effect on T lymphocytes, but also via an effect on the central antigen presenting cells, the dendritic cells (26). In vitro, the presence of 1,25(OH) 2 D or an analog results in the generation of dendritic cells with specific characteristics, such as less IL12 secretion, less CD80/CD86 expression, less MHC II expression, and most importantly less stimulation of effector T cells and specific generation of regulator T cells (27,28). Thus, a second possible avenue to exploit the potential beneficial immune modulatory effects of vitamin D is the auto-transfer of ex vivo 1,25(OH) 2 D (or analog)-exposed dendritic cells generated from peripheral blood monocytes from patients with T1DM.…”