The recently discovered cytokine IL-27 belongs to the IL-6/IL-12 family of cytokines and induced proliferation of naive CD4(+) T cells and the generation of a Th1-type adaptive immune response. ...Although binding of IL-27 to the cytokine receptor WSX-1 was demonstrated, this interaction proved insufficient to mediate cellular effects. Hence, IL-27 was believed to form a heteromeric signaling receptor complex with WSX-1 and another, yet to be identified, cytokine receptor subunit. In this study, we describe that WSX-1 together with gp130 constitutes a functional signal-transducing receptor for IL-27. We show that neither of the two subunits itself is sufficient to mediate IL-27-induced signal transduction, but that the combination of both is required for this event. Expression analysis of WSX-1 and gp130 by quantitative PCR suggests that IL-27 might have a variety of cellular targets besides naive CD4(+) T cells: we demonstrate gene induction of a subset of inflammatory cytokines in primary human mast cells and monocytes in response to IL-27 stimulation. Thus, IL-27 not only contributes to the development of an adaptive immune response through its action on CD4(+) T cells, it also directly acts on cells of the innate immune system.
Because of their genetic and biological similarity to humans, non-human primates are the best pre-clinical models for testing the efficacy and safety of gene therapy systems. However, the presence of ...endogenous simian foamy virus infection in nearly all non-human primates kept in captivity complicates foamy virus (FV) vector stem cell transduction studies in these animals. A major concern is that repopulating cells exposed to FV vector stocks will elicit an immune response in non-human primate hosts. Though human serum does not inactivate prototype foamy virus (PFV) vectors, a one hour incubation of PFV vector stock in the presence of serum samples from Papio Cynophalus (baboon), Macaca Mulatta (rhesus macaque), or Macaca Fasicularis (long-tailed macaque) results in a 75–100% drop in titer. To overcome this serum mediated inactivation we sought to pseudotype PFV vectors in the feline foamy virus (FFV) envelope. The wild-type envelope from the FUV strain of FFV does not pseudotype our PFV vectors. Therefore we generated chimeras with regions of both the FFV and PFV envelope. By substituting portions of the FFV envelope leader peptide sequence and membrane spanning domain with corresponding PFV envelope regions we generated chimeric envelopes capable of high titer (105–106 FFU/ml) PFV vector production. Serum samples from Macaca Mulatta produced less inactivation of the FFV pseudotyped than the PFV pseudotyped vectors. Furthermore, both the PFV and FFV pseudotyped vectors demonstrated efficient transduction of baboon mesenchymal stem cells (27–43%) and baboon embryonic stem cells (37–40%). However, the FFV pseudotyped vectors transduced both human and baboon CD34+ cells less efficiently than the PFV pseudotyped vectors. We plan to test PFV vectors pseudotyped by other FV envelopes for inactivation by primate serum, and for their ability to transduce primate hematopoietic cells.
An efficient Th1-driven adaptive immune response requires activation of the T cell receptor and secretion of the T cell stimulatory cytokine IL-12 by activated antigen-presenting cells. IL-12 ...triggers Th1 polarization of naive CD4
+ T cells and secretion of IFN-γ. We describe a new heterodimeric cytokine termed IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. IL-27 is an early product of activated antigen-presenting cells and drives rapid clonal expansion of naive but not memory CD4
+ T cells. It also strongly synergizes with IL-12 to trigger IFN-γ production of naive CD4
+ T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.
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