Interferon-α-Conditioned Human Monocytes Combine a Th1-Orienting Attitude with the Induction of Autologous Th17 Responses: Role of IL-23 and IL-12

Abstract

IFN-α exerts multiple effects leading to immune protection against pathogens and cancer as well to autoimmune reactions by acting on monocytes and dendritic cells. We analyzed the versatility of human monocytes conditioned by IFN-α towards dendritic cell differentiation (IFN-DC) in shaping the autologous T-helper response. Priming of naïve CD4 T cells with autologous IFN-DC in the presence of either SEA or anti-CD3, resulted, in addition to a prominent expansion of CXCR3+ IFN-γ-producing CD4 Th1 cells, in the emergence of two distinct subsets of IL-17-producing CD4 T cells: i) a predominant Th17 population selectively producing IL-17 and expressing CCR6; ii) a minor Th1/Th17 population, producing both IL-17 and IFN-γ. After phagocytosis of apoptotic cells, IFN-DC induced Th17 cell expansion and IL-17 release. Notably, the use of neutralizing antibodies revealed that IL-23 was an essential cytokine in mediating Th17 cell development by IFN-DC. The demonstration of the IFN-DC-induced expansion of both Th1 and Th17 cell populations reveals the intrinsic plasticity of these DC in orienting the immune response and provides a mechanistic link between IFN-α and the onset of autoimmune phenomena, which have been correlated with both IL-17 production and exposure to IFN-α.

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

“…40,41 The role of in vivo occurring IFN-DCs in human pathologic conditions is strongly supported by several studies. [40][41][42][43] These observations may be linked to the ability of IFN-DCs to act as polyfunctional APCs, endowed with a potent attitude to bias the Th response toward the Th1 type 1 and concomitantly inducing the emergence of autologous Th17 CD4 ϩ T cells, as we have demonstrated recently, 44 thus providing a possible mechanistic interpretation for the observed coupling of protective immunity with autoimmunity during IFN-␣ therapy. 45 The data presented here add further insight into this phenomenon by characterizing the mechanisms of the peculiar efficiency of IFN-DCs in mediating the cross-priming of CD8 ϩ T cells.…”

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

“…In our experimental conditions, the absence of any detectable paracrine secretion of IL-12 by IFN-DC suggests that DC/NK cross-talk does not rely on this cytokine. We previously demonstrated that IFN-DC spontaneously produce an array of inflammatory cytokines, including TNF-a, IL-1b, IL-6, IL-23, and IL-27, promoting a Th1-type response, but also a Th17-type response (10,28). Nonetheless, it cannot be ruled out that other molecules or cytokines expressed by IFN-DC or distinct T cell subsets may contribute to NK cell activation and enhancement of lytic activity toward lymphoma cells.…”

TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7

“…[4][5][6] Recent studies have shown that DCs conditioned with cytokines TNF-a, 17 TGF-b 18 and IFN-a 19 show an altered ability to polarize T cells into Th1, Th2 and Th17 subsets. Here, we found that TGF-b-conditioned murine bone marrow-derived dendritic cells (BMDCs) had reduced ability to trigger Th1 commitment but promoted production of IL-10 in T cells as compared with lipopolysaccharides (LPS) or TNF-a-conditioned BMDCs ( Supplementary Figures S1A and B).…”

“…Previous studies have indicated that the nature of cytokine secretion by antigen-pulsed DCs 10,21 or antigen-unpulsed DCs 18,19 may determine the polarization of Th cells toward Th1, Th2, Treg or Th17 lineages. The expression of these cytokines is carefully regulated by the different transcription factors, such as NF-kB and AP-1.…”