IL-27, a Heterodimeric Cytokine Composed of EBI3 and p28 Protein, Induces Proliferation of Naive CD4+ T Cells

Abstract

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-gamma. 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-gamma production of naive CD4(+) T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.

Treatment-naïve HPV+ head and neck cancers display a T-cell-inflamed phenotype distinct from their HPV- counterparts that has implications for immunotherapy

“…25 IL23A levels were higher in HPV+ HNSCC than HPV- tumors and normal samples (Figure 5B). Moreover, Epstein-Barr virus-induced gene 3 (EBI3) transcripts that encode a component of IL27 (a cytokine that synergizes with IL12 and induces IFN-γ production by naïve CD4 + T-cells) 26 were significantly higher in HPV+ than HPV- tumors and normal samples (Figure 5B). We were not able to analyze the other two genes within the IL12 family of cytokines–IL12B and IL27A–because their RNA transcripts were not detectable in the majority of tumor and normal control samples.…”

New insights into IL-12-mediated tumor suppression

“…155,156 As IL-27 acts only on naive T cells, the concentrations of IL-27-induced pro-inflammatory cytokines are presumably not high enough to induce the appearance of adverse side effects. 157 IL-35 was initially described as a Treg-specific cytokine with potent immunosuppressive properties. 158 Studies conducted with IL-35-overexpressing cancer cells reported a role for IL-35 in promoting tumor growth through the suppression of T-cell responses.…”

Regulation of cytokine production during phagocytosis of apoptotic cells

“…IL-27 appears to be produced early by activated antigenpresenting cells. It is able to induce clonal proliferation of naïve but not memory CD4 + T cells and synergizes with IL-12 in IFN-g production by naïve CD4 + T cells [48]. Recently, an orphan receptor was described with 26% homology and 37% similarity to the IL-12Rβ2 subunit and to gp130, respectively, designated TCCR [49] or WSX-1 [50].…”

“…Recently, an orphan receptor was described with 26% homology and 37% similarity to the IL-12Rβ2 subunit and to gp130, respectively, designated TCCR [49] or WSX-1 [50]. This receptor was identified as one of the receptor subunits for IL-27 and is necessary but not sufficient for IL-27 function [48]. It has been suggested that IL-27 and IL-12 function sequentially in initiating and maintaining Th1 responses, respectively [48,50].…”

“…This receptor was identified as one of the receptor subunits for IL-27 and is necessary but not sufficient for IL-27 function [48]. It has been suggested that IL-27 and IL-12 function sequentially in initiating and maintaining Th1 responses, respectively [48,50]. Recombinant IL-27 expressed from tumor cells has been shown to elicit potent tumor-specific immune responses in vivo and result in complete regression of orthotopic primary and metastatic murine neuroblastoma tumors [51], and Colon 26 murine colon carcinoma [52].…”