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.

Summary Interferon (IFN)‐λ1 [interleukin (IL)‐29] is a member of the interferon lambda family (also known as type III interferons), whose members are distantly related to both the type I interferons and members of the IL‐10 family. While IFN‐λ1 has significant antiviral activity, it is also becoming apparent that it has important immunoregulatory properties, especially with regard to the T helper type 2 (Th2) response. Previously, we have shown that IFN‐λ1 is capable of down‐regulating IL‐13 production in an IFN‐γ‐independent manner and that this is mediated in part via monocyte‐derived dendritic cells. Here, we have extended our knowledge of IFN‐λ1 regulation of the human in vitro Th2 response by examining the regulation of three major Th2 cytokines, IL‐4, IL‐5 and IL‐13, by IFN‐λ1. Our results reveal that IFN‐λ1 preferentially inhibits IL‐13 production, compared with IL‐4 or IL‐5. Levels of IL‐13 mRNA, the amount of secreted IL‐13 protein and numbers of IL‐13‐positive CD3+ CD4+ cells were all significantly diminished by IFN‐λ1. IFN‐λ1 significantly decreased some aspects of IL‐4 and IL‐5 production, but its effects were not as consistent as those seen on IL‐13. IFN‐λ1 was also effective at decreasing IL‐13 secretion under conditions designed to support the generation of Th2 cells. Irrespective of whether Concanavalin‐A or T‐cell‐stimulatory microbeads were used, IFN‐λ1 markedly diminished IL‐13 secretion in cultures where IL‐4 had been added. Thus, IFN‐λ1 appears to be an inhibitor of human Th2 responses whose action is primarily directed towards IL‐13 but which may also affect Th2 responses generally and does not invoke a complementary elevation of IFN‐γ secretion.

Interferon lambda-1 (IFN-l1), the prototype Type-III interferon, has antiviral functions similar to those of the Type-I interferons, IFN-a and IFN-b. However, IFN-l1 is capable of signaling through almost all STAT molecules and so it is possible that it may have novel immunoregulatory functions in addition to antiviral ones. From a range of chemokines tested, IFN-l1 elevated mRNA levels of only 'Monokine induced by IFN-gamma' (MIG/CXCL9), 'IFN-gamma inducible protein-10' (IP-10/CXCL10) and 'IFN-gamma inducible T-cell a chemoattractant' (I-TAC/CXCL11) from human peripheral blood mononuclear cells. As their names suggest, these chemokines are also induced by IFN-g, the only member of the Type-II interferon family. This action of IFN-l1 did not depend on intermediate induction of IFN-g and is therefore, likely to be independent of IFN-g. Further, our results suggest that donors responded to IFN-l1 stimulation either 'early' or 'late'. Overall the action of IFN-l1 was similar to that previously reported for IFN-g and may invite more detailed investigation of the role of IFN-l1 at the innate/adaptive interface.

No abstract

Interferon lambda one ((IFN-λ1, IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-λ1, 2 and 3. These ligands use the same hererodimeric receptor, comprised of the CRF2-12 (IFN-λ1/IL-28Rα) chain and the CRF2-4 (IL-10Rβ) chains. Like their close relatives the Type-I interferons, IFN-λ1, 2 and 3 promote the phosphorylation of STATs 1&2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit anti-viral activity in vitro. Their use of the IL-10Rβ chain and their ability to phospohrylate STATs 3, 4 & 5 suggested that they might also exhibit immunoregulatory activity; their antiviral activity led us to hypothesize that this might be directed towards the Th1/Th2 system. Here, we demonstrate that IFN-λ1 altered the activity of human Th cells in three experimental systems: mitogen stimulation, MLR and the stimulation of naive T-cells by monocyte-derived dendritic cells(mDC). In general the inclusion of IFN-λ1 consistently led to a marked diminution of secreted IL-13 (15/16 donors) with occasional (5/16 donors) coincident, modest elevation of secreted IFN-γ. IL-13 secretion was 100-fold more sensitive to IFN-λ1 than was IFN-γ secretion. IFN-λ1 was able to alter Th-biasing and when naive T-cells were exposed to allogeneic mDC that had been developed in the presence of IFN-λ1, secreted IL-13 was again markedly and consistently reduced. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-λ1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion in human in vitro cell culture.