Vitamin D3 Priming of Dendritic Cells Shifts Human Neutrophil-Dependent Th17 Cell Development to Regulatory T Cells

Abstract

Vitamin D3 (VD3) is a potential adjuvant for use in tolerogenic vaccine formulations that target dendritic cells (DCs) for the treatment of chronic inflammatory disorders, e.g., autoimmune diseases. These disorders are often associated with enhanced activity of IL-17-producing T helper 17 (Th17) cells which develop in a DC-driven and neutrophil-dependent fashion. Here, we investigated the effect of VD3 on Candida albicans-specific human T-cell differentiation, since C. albicans is a model pathogen for Th17 cell development. VD3 priming of DCs restricted neutrophil-dependent Th17 cell development and neutrophil-independent Th1 cell formation from naive CD4+ T cells. In line with this, the production of Th1/Th17-polarizing cytokines IL-12 and IL-23 by DCs was reduced by VD3 priming. Development of both FoxP3+CD127lowCD25+ Tregs and IL-10-producing T cells was significantly enhanced in VD3-primed conditions, even in the presence of neutrophils. ICOS+ Tregs, major IL-10 producers, CD69+FoxP3+, and TIGIT+FoxP3+ Tregs were significantly induced by VD3 priming as well. Our data support the potential use of VD3 as an adjuvant to induce tolerance in the treatment of autoimmune disorders, including those in which neutrophils are involved in pathogenesis, since we show that Treg development is enhanced by VD3 even in the presence of neutrophils, while Th17 cell development is restricted.

Estrogen Protects against Renal Ischemia-Reperfusion Injury by Regulating Th17/Treg Cell Immune Balance

“…For specific Treg types, IL-10 production is crucial for their suppressive function. We used intracellular cytokine staining of IL-10 to define the proportion of Treg cells [ 43 ]. New insights on the immunopathogenesis of kidney diseases have indicated a role of change of the Th17/Treg axis [ 18 , 44 ].…”

Vitamin D and Chronic Obstructive Pulmonary Disease

“…In stable COPD patients, IL-17 was expressed in the bronchial mucosa at a higher level than in the control group, and Th17 was crucial to the emergence and progression of chronic inflammation in COPD (24). 1,25-(OH)2D3 can greatly reduce Th17 generation, which is advantageous for disorders caused by T cell-mediated immunity (25). These investigations demonstrated that 1,25-(OH)2D3 can block the development and occurrence of illnesses that are mediated by Th1/Th17 cells.…”

Retinoic acid‐loaded liposomes induce human mucosal CD103+ dendritic cells that inhibit Th17 cells and drive regulatory T‐cell development in vitro

“…A total of 50,000 DCs was cocultured with 100,000 autologous neutrophils and 50,000 naïve CD4 + T cells in Candida albicans hyphae-coated 96-well plates (Costar). Hyphae plates were generated as described before [49]. At day 4-5, proliferating T cells were transferred to flat-bottom 48-well plates (Costar) and refreshed every 2 days with medium supplemented with rhIL-2 (Cetus) at a final concentration of 10 U/mL.…”

“…In addition, 100,000 CD4 + T cells were stimulated in triplicate with soluble anti-human CD3 and CD28 in 200 µL of IMDM/10 % FCS for analysis of IL-10 in 24-h supernatants, as done previously [50]. For phenotyping of Tregs, a panel of antibodies was used as recently described [49].…”

“…Resting T cells were additionally stained with anti-LAG-3-PE-CF594 (Biolegend) and anti-CD49b in a separate panel. The antibody clone 11C3C65 of LAG-3 was used in this study, while clone T47-530 (BD) was used in a previous study where LAG-3 was not detected [49]. A total of 50,000 cells was analyzed in the live gate on the SP6800 Spectral Analyzer (Sony) or FACS Fortessa.…”