Synergistic Effects of Interferon-γ and Vitamin D3 Signaling in Induction of ILT-3highPDL-1high Tolerogenic Dendritic Cells

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.

Cytokines, 25-OH vit D and disease activity in patients with juvenile-onset systemic lupus erythematosus

“…The active state of Vit D and IFN-γ are both pleiotropic endogenous immune modulators and may be useful in immunogenicity and immune tolerance. 23…”

“…The active state of Vit D and IFN-c are both pleiotropic endogenous immune modulators and may be useful in immunogenicity and immune tolerance. 23 Vit D prevents the development of autoantibody and reduces the number as well as the action of dendritic cell-related pathways, thus it causes suppression of T cell activation. Active vitamin D;1,25(OH)D has additional immunomodulatory activities, it prevents the proliferation of B cells before possessing the capacity to secrete immunoglobulin.…”

Regulatory Dendritic Cells, T Cell Tolerance, and Dendritic Cell Therapy for Immunologic Disease

“…However, not all inhibitory factors expressed by a DCreg necessarily contribute to the cell’s regulatory activities. Thus, vitamin D/IFNγ-induced human DCreg express IL-10, HLA-G, PD-L1 and low levels of FasL, but among these it was only their expression of PD-L1 that was reported as integral to the cell’s regulatory activities ( 60 ). It is also apparent that inhibitory receptors can play more than one role in immune tolerance.…”

1,25-dihydroxyvitamin D3 regulates t helper and b lymphocyte responses substantially in drug-naive primary Sjögren’s syndrome patients’ mononuclear cells

“…This inhibitory effect was occurred with the enhanced expression of CTLA-4, PD1 or PD-L1 on regulatory cells in the immune system, and also with the suppressive effect of IL-10, which is produced by Treg cells (28,29). Additionally, IFN- can synergistically enhance the suppression in proliferative responses with vitamin D3 by expressions of immunoglobulin-like transcript (ILT)-3 and programmed death ligand (PDL)-1 on tolerogenic DCs (30). In the present study, we observed reduced number of IFN- secreting Th lymphocytes in both drug-naïve and pSS treated patients, while the reduction was striking in drug-naïve patients.…”