IL-27 Receptor Signaling Regulates CD4+ T Cell Chemotactic Responses during Infection

Abstract

IL-27 exerts pleiotropic suppressive effects on naïve and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4+ T cell chemotactic responses, as a mechanism to reduce T cell-dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, pro-inflammatory infection, we demonstrate that IL-27R signalling represses chemotaxis of infection-derived splenic CD4+ T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4+ T cells from malaria-infected, IL-27R deficient (WSX-1−/−) mice than from infected wild type (WT) mice. We find that IL-27 signalling suppresses splenic CD4+ T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4+ T cell sub-types, including Th1 cells, and also by controlling the overall composition of the CD4+ T cell compartment. Diminution of the Th1 response in infected WSX-1−/− mice in vivo by neutralisation of IL-12p40 attenuated CCR5 expression by infection-derived CD4+ T cells and also reduced splenic CD4+ T cell chemotaxis towards CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4+ T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings.

Oral delivery of oligomeric procyanidins in Apple Poly® enhances type I IFN responses in vivo

“…Anti-inflammatory responses following ingestion of some polyphenol-containing supplements may be, in part, a result of enhanced type I IFN responses through enhanced expression of anti-inflammatory cytokines IL-10 and IL-27. IL-27R signaling, in particular, has been shown recently to decrease specifically inflammatory cytokine expression, primarily IFN-␥, and trafficking by CD4 ϩ T cells [25,26]. These cells are a primary source of inflammation in the mouse model of colitis [27].…”

Role of Chemokines and Trafficking of Immune Cells in Parasitic Infections

“…Control of inflammation during parasitic infection is achieved mostly by Treg cells, IL-10 producing CD4+ T cells, and IL-27R signaling [126–128]. Recently, Couper and colleagues have demonstrated that IL-27 is responsible for inhibiting the CCL4 and CCL5 responding CD4+ T cells that migrate to Plasmodium infection in the liver and does so by directly downregulating CCR5 expression [129]. Surprisingly, considering the significant volume of studies investigating many of these immunomodulatory pathways, there is little understanding of chemokine recruitment of regulatory cell populations during parasitic infection [95].…”

Regulation of immunopathogenesis during Plasmodium and Toxoplasma infections: more parallels than distinctions?

“…The mechanisms underlying the ability of IL-27 to regulate Th1 inflammatory T cells during Plasmodium infection are just now becoming clear. In contrast to its ability to induce specific populations of Tregs in the Toxoplasma -infected gut, IL-27 signaling in effector T cells during blood stage Plasmodium infection appears to suppress inflammatory Th1 cell responsiveness to specific chemokines and cytokines [48,49]. A recent report showed that IL-27 signaling in highly polarized Th1 cells led to marked reductions in the expression of the CCR5 chemokine receptor.…”

“…A recent report showed that IL-27 signaling in highly polarized Th1 cells led to marked reductions in the expression of the CCR5 chemokine receptor. The authors contend that dysregulation of CCR5-dependent T cell chemotaxis contributes to the ability of IL-27 to suppress inflammatory Th1 T cell migration to the spleen during Plasmodium infections [49]. Moreover, a subsequent study examining pathogenic Th1 cells induced by P. berghei infection found that IL-27 limited T cell responsiveness to IL-12 [48], which is a critical positive regulator of Th1 cell differentiation and survival as discussed above.…”