Abstract
In the past, interferon (IFN)-γ and vitamin D3 (vit D3) have both been associated with induction of tolerogenic characteristics in human dendritic cells (DCs). Although there are only a few reports on interdependency of their actions, the interplay between IFN-γ and vit D3 has been clearly demonstrated in certain aspects of immune reactivity. Since both agents have been associated with regulation of immune responses, we set out to examine their functional and mechanistic interactions in context of principal regulators of immunity, the DCs. Combined treatment with vit D3 and IFN-γ caused an extensive expression of immunoglobulin-like transcript (ILT)-3 and programmed death ligand (PDL)-1 on γ/D3DCs, significantly greater than that caused by vit D3 alone. Such γ/D3DCs retained all general DC characteristics. After CD40 ligand-induced activation, they produced increased amounts of IL-10 with almost absent production of IL-12p70. On the other hand, the co-stimulatory potential of γ/D3DCs was weak, with cells possessing the capacity to inhibit CD4+ T cell, CD8+ T cell, as well as memory T cell responses. Naive CD4+ T cells stimulated with γ/D3DCs produced increased amounts of IL-10 with concomitantly low IFN-γ production, upon T cell receptor activation. Additionally, γ/D3DCs completely inhibited granzyme B expression by CD8+ T cells. The percentage of FoxP3-positive cells in co-cultures with naive CD4+ T cells was significantly higher where γ/D3DCs were used as stimulators compared to DCs treated with vit D3 alone and it could be partially reversed by PDL-1 blockade. Interestingly, γ/D3DCs were inefficient at suppressing mDC-induced CD4+ T cell proliferation, but were twice as effective as D3DCs at suppressing mDC-induced CD8+ T cell proliferation. Blockade of indoleamine-2,3-dioxygenase did not reduce the tolerogenic phenotype induced by IFN-γ and vit D3 treatment. Examination of signaling pathways activation revealed a tendency toward increased ERK and Akt phosphorylation in γ/D3DCs. Inhibition of MEK/ERK and PI3K/mTOR pathways significantly reduced the expression of ILT-3 and PDL-1 on γ/D3DCs. In summary, we present the first evidence for existing synergy between IFN-γ and vit D3 in shaping a unique tolerogenic DC activation state.
Highlights
The active metabolite of vitamin D (1,25dihidroxycholecalciferol or vitamin D3 (vit D3)) and interferon (IFN)-γ are both pleiotropic endogenous immune modulators and can assist in immunogenic and tolerogenic processes
To determine whether the low allo-stimulatory potential of γ/D3DCs is still retained after exposure to immunogenic signals, we performed an allogeneic co-culture where D3DCs or γ/D3DCs were used as stimulators after 24 h exposure to LPS (Figure 3E)
Either immature DCs (iDCs), mature DCs (mDCs), γDCs, D3DCs, or γ/D3DCs were used as stimulators in an allogeneic co-culture with naive CD4+CD45RA+ T cells
Summary
The active metabolite of vitamin (vit) D (1,25dihidroxycholecalciferol or vit D3) and interferon (IFN)-γ are both pleiotropic endogenous immune modulators and can assist in immunogenic and tolerogenic processes. As shown by Vidal et al, IFN-γ treatment induces increased nuclear translocation of the vit D receptor (VDR) [17] In this manner, increased nuclear presence of both VDR and STAT-1 leads to functional STAT-1/VDR interactions, which in turn enhances IFN-γ signaling by preventing STAT-1 dephosphorylation. The functional outcomes of interactions between IFN-γ and vit D3 seem to differ in terms of immune reactivity, suggesting dependence on pathology in question and immune cell types involved. Due to the fact that pathways of both endogenous immune modulators have been shown to interact in other cell types at least to a certain extent, we set out to explore their potential mutual contribution in regulating the fundamental aspects of DC function
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
