Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

Abstract

Interferon lambda-1 (IFN-l1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-l1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-l-R1/IL-28Ra) and CRF2-4 (IL10-R-b) chains. Like their close relatives, the Type-I interferons, IFN-l1, 2 and 3, promote the phosphorylation of STAT1 and STAT2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit antiviral activity in vitro. Their use of the IL10-R-b chain and their ability to phosphorylate STAT3, STAT4 and STAT5 suggested that they may also exhibit immunomodulatory activity; their antiviral action led us to hypothesize that this activity might be directed toward the Th1/Th2 system. Here, we have demonstrated that IFN-l1 altered the activity of Th cells in three separate experimental systems: (i) mitogen stimulation, (ii) mixed-lymphocyte reaction (MLR) and (iii) stimulation of naive T cells by monocyte-derived dendritic cells (mDC). In Con-A stimulation assays, the inclusion of IFN-l1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-g. IL-13 secretion was 100-fold more sensitive to IFN-l1 than was IFN-g secretion. These observations were also made in the allogeneic two-way MLR. IFN-l1 was able to alter cytokine-mediated Th biasing and when naive T cells were exposed to allogeneic mDC that had been matured in the presence of IFN-l1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-g was largely unaltered. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-l1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion.

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

“…We confirmed the broad expression pattern of the IFNAR system, and found that among the cell types examined, that pDCs were the only hemopoietic cell type that responded to IFN-. Others have reported that human monocytes, blood monocyte-derived DCs, and murine intrahepatic CD3 Ϫ DX5 ϩ NK cells respond to IFN-or express the receptor chains (28,29,47,49). Therefore, we conclude that only few cell types of the hemopoietic compartment are responsive to IFN-, although we cannot exclude that expression of the type III IFN receptor system may be induced by cell differentiation and activation in a broader spectrum of cells.…”

“…For instance, treatment with IFN-1 induces expression of a subset of inflammatory cytokines in human monocytes and macrophages (47,48). Others have reported that human blood monocytes gain responsiveness to IFNduring differentiation to DCs, and that these DCs induce proliferation of regulatory T cells (29) and modulation of the Th1/Th2 response (49). In a different study it was shown that intrahepatic CD3 Ϫ DX5 ϩ NK cells express the IFN-receptor chains and contribute to the antitumor activities of IFN- (28).…”

Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines

“…In contrast to these investigations, some studies did propose direct effects of IFN-ls on monocytes, 32,33 DCs 34 and T cells. [35][36][37][38][39][40] We currently cannot explain the discrepancy in these observations in terms of whether IFN-ls influence, for example, monocytes or T cells. As we demonstrated, it seems that the preactivation with cell-specific stimuli or virus-mimicking agents could not confer any clear responsiveness to these cytokines on peripheral immune cells.…”

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

“…These effects can be direct on CD4 + T cells or indirect, via MDDC. Further, IFN-l1 secretion is itself Th2 cytokine responsive (11,12,(21)(22)(23). Recent studies also showed that IFN-l1 expression is reduced in alveolar macrophages and bronchial epithelial cells of rhinovirus-infected asthmatic individuals (24,25).…”