Interferon-λ–treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells

Abstract

The interferons (IFN-s), also known as IL-28 and IL-29, are coexpressed with IFN-␤ after Toll-like-receptor (TLR) stimulation in human monocyte-derived dendritic cells (DCs). IFN-shares with type I IFNs an intracellular signaling pathway that drives the expression of a common set of genes. However, IFN-signaling is initiated through a membrane receptor system distinct from that of type I IFNs. Because IFNs produced by DCs in response to TLR stimulation are critical in the differentiation and maturation of DCs, we sought to investigate whether IFNexhibits specific effects on DC differentiation. In this work, we show that DCs acquire IFN-responsiveness through the expression of the specific IFN-receptor chain during their differentiation from monocytes. IFN--treated DCs express high levels of major histocompatibility complex class I (MHC class I) and MHC class II but low levels of costimulatory molecules. However, they express CCR7 and acquire the ability to migrate to lymph nodes when intravenously injected into SCID/Bg mice. In mixed lymphocyte reaction (MLR) cultures, IFN--treated DCs specifically induced IL-2-dependent proliferation of a CD4 ؉ CD25 ؉ Foxp3 ؉ T-cell subset with contact-dependent suppressive activity on T-cell proliferation initiated by fully mature DCs. IFN-s are thus able to generate tolerogenic DCs, an activity that could thwart IFN-␤ functions. IntroductionThe function of type I interferons (IFNs) in the regulation of the innate immune response is clearly established. [1][2][3] More recently, the importance of the type I IFN family (several ␣ subtypes and one ␤ subtype) in the generation of T cell-mediated adaptive immunity has emerged. 4,5 The fact that IFN-␤ is produced by dendritic cells (DCs) upon Toll-like-receptor (TLR) stimulation and can act as a differentiation and maturation factor on DCs has led to the concept that IFN-␤ is a cytokine linking innate and adaptive immunity. 6 However, type I IFNs are never produced alone: TLR-3 and TLR-4 stimulation of human monocyte-derived DCs, by their respective ligands, also induce the production of IFN-␤ and IFN-s. 7 The IFN-family was recently described. [8][9][10] It has 3 members: 1, 2, and 3, also known as IL-29, IL-28A, and IL-28B, respectively. IFN-s exhibit several common features with type I IFNs, including the ability to establish an antiviral state in sensitive cell lines, probably because IFN-s share with type I IFNs an intracellular signaling pathway that drives the expression of a common set of IFN-stimulated genes (ISGs). 11,12 However, IFNsignaling is initiated through a membrane receptor system distinct from that of type I IFN and composed of a unique IFN-LR1 subunit and the IL-10R2 chain, which is also part of the IL-10, IL-22, and IL-26 receptors. 13 The different receptor use of type I IFNs and IFN-s could give rise to unique signaling pathways in addition to recruitment of Stat1 and Stat2, both of which are activated by type I IFN and IFN-s through the Tyk2 and Jak1 kinases. Another important difference between type I IFN ...

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

“…At present, we can only speculate on the potential role of this slight increase in IL-12 production by mDCs. A recent report 43 described the inability of IFN-l1 to lead to the development of a mature DC phenotype, producing instead an intermediate phenotype, described as 'tolerogenic'; our data would not contradict this report. Clearly, however, it does not interfere with the ability of IFN-l1 to inhibit IL-13 secretion from T cells stimulated by mDCs and we believe it is likely that the major role of IFN-l1 is on the development of monocytes to intermediate DCs rather than on the final maturation of these cells.…”

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).…”

“…Although this also involves induction of tumor apoptosis (28), it seems primarily to be mediated by host immune cells, with NK cells being ascribed particularly important roles (27,28). Moreover, IFN-seems to have immunomodulatory functions, because IFN--stimulated human monocyte-derived dendritic cells (DCs) induce proliferation of FOXP3-expressing suppressor T cells with contact-dependent suppressive activity on T cell proliferation (29). This phenomenon may explain why IFN-has suppressive activity on CD4 T cells induced by respiratory syncytial virus (30).…”

Identification of the Zebrafish IFN Receptor: Implications for the Origin of the Vertebrate IFN System

“…In amniotes, this new type I IFN system has superseded the ancestral IFN-system as the major innate antiviral system. The present IFN-system of mammals can probably be viewed more as a tissue-specific antiviral system (4) and is also clearly involved in the regulation of the adaptative immune system (41). Further diversification of the type I IFN system has mainly consisted in ligand diversification in the context of a fixed receptor architecture (40,42).…”