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

Abstract

Interferon lambda-1 (IFN-λ1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-λ1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-λ-R1/IL-28Rα) and CRF2-4 (IL10-R-β) chains. Like their close relatives, the Type-I interferons, IFN-λ1, 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-β 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-λ1 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-λ1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-γ. IL-13 secretion was 100-fold more sensitive to IFN-λ1 than was IFN-γ secretion. These observations were also made in the allogeneic two-way MLR. IFN-λ1 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-λ1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-γ was largely unaltered. 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.