Interferon (IFN)-1, -2, and -3 are the latest members of the class II cytokine family and were shown to have antiviral activity. Their receptor is composed of two chains, interleukin-28R/likely interleukin or cytokine or receptor 2 (IL-28R/LICR2) and IL-10R␤, and mediates the tyrosine phosphorylation of STAT1, STAT2, STAT3, and STAT5. Here, we show that activation of this receptor by IFN-1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs. We used IL-28R/ LICR2-mutated receptors to identify the tyrosines required for STAT activation, as well as antiproliferative and antiviral activities. We found that IFN-1-induced STAT2 tyrosine phosphorylation is mediated through tyrosines 343 and 517 of the receptor, which showed some similarities with tyrosines from type I IFN receptors involved in STAT2 activation. These two tyrosines were also responsible for antiviral and antiproliferative activities of IFN-1. By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues. Taken together, these observations extend the functional similarities between IFN-s and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines.The interleukin-28 receptor (IL-28R, also named LICR2 and CRF2-12) 1 is a member of the class II cytokine receptor family (CRF2) (1-3), which includes receptors for type I and type II IFNs (IFNAR1, IFNAR2, IFNGR1, and IFNGR2), tissue factor, and receptors for IL-10-related cytokines: IL-10R␣, IL-22R/ CRF2-9, IL-10R␤/CRF2-4, IL-20R␣/CRF2-8, IL-20R␤/CRF2-11, and IL-28R/LICR2 (4 -7). When IL-28R associates with IL-10R␤, it creates a high affinity binding complex for IFN-1, -2, and -3 (also called IL-29, IL-28a, and IL-28b) (2, 3). These cytokines share limited sequence similarity with type I IFNs. Like type I IFNs, they are expressed by human peripheral blood mononuclear cells and dendritic cells upon infection with viruses or stimulation with poly(I:C) (2, 3, 8).Although they use distinct receptor chains, which have no detectable homology in their intra-cytoplasmic domain, type I IFNs and IFN-s activate similar signal transduction pathways. Chimeric receptors containing the intracellular portion of IL-28R/LICR2 could mediate JAK1 (Janus kinase 1) activation, as well as tyrosine phosphorylation of STAT factors (1, 2), including STAT2, whose activation was considered to be a specific characteristic of the type I IFN response (9, 10).Most importantly, IFN-1, -2, and -3 protected several cell lines against viral infection and up-regulated major histocompatibility complex class I antigen expression (2, 3). Receptors for type I IFNs are composed of two chains, IFNAR1 and IFNAR2, in which 3 tyrosines seem to be essential to recruit STAT2: Tyr 466 in IFNAR1, and Tyr 337 and Tyr 512 in IFNAR2 (11, 12). Here, we introduced point mutations into the cytoplasmic domain of IL-28R/LICR2 to determine which tyrosines are involved in different ...

Keratinocytes have a pivotal role in the regulation of immune responses, but the impact of antigen presentation by these cells is still poorly understood, particularly in a situation where the antigen will be presented only in adult life. Here, we generated a transgenic mouse model in which keratinocytes exclusively present a myelin basic protein (MBP) peptide covalently linked to the major histocompatibility complex class II β-chain, solely under inflammatory conditions. In these mice, inflammation caused by epicutaneous contact sensitizer treatment resulted in keratinocyte-mediated expansion of MBP-specific CD4(+) T cells in the skin. Moreover, repeated contact sensitizer application preceding a systemic MBP immunization reduced the reactivity of the respective CD4(+) T cells and lowered the symptoms of the resulting experimental autoimmune encephalomyelitis. This downregulation was CD4(+) T-cell-mediated and dependent on the presence of the immune modulator Dickkopf-3. Thus, presentation of a neo self-antigen by keratinocytes in the inflamed, adult skin can modulate CD4(+) T-cell auto-aggression at a distal organ.

Mesenchymal stem cells (MSCs) are known to limit immune responses in vivo by multiple soluble factors. Dickkopf-3 (DKK3), a secreted glycoprotein, has recently been identified as a novel immune modulator. Since DKK3 has been reported to be produced by MSCs, we investigated whether DKK3 contributes to the immune suppression of anti-tumor responses by MSCs. Whereas wild-type MSCs inhibited immune responses against two different transplantation tumors, DKK3-deficient MSCs did not affect the rejection process. Increased CD8+ T cell and reduced M2-type macrophages infiltration was observed in tumors inoculated together with DKK3-deficient MSCs. Thus, DKK3 could alter the composition of the tumor stroma, thereby supporting the MSCs-mediated suppression of immune responses against these tumor transplants.