IL-27 in Human Secondary Lymphoid Organs Attracts Myeloid Dendritic Cells and Impairs HLA Class I–Restricted Antigen Presentation

Abstract

Different cytokines play crucial roles in inflammation and in polarizing immune responses, including IL-27 that exerts pro- and anti-inflammatory functions. Although the activity of IL-27 is well characterized in murine immune cells, only limited information is available regarding the natural cellular sources of IL-27 in humans and its effects on human immune cells. Dendritic cells (DCs) are the most potent professional APCs that in the immature state are positioned throughout peripheral tissues by acting as sentinels, sensing the presence of Ags. Activated DCs migrate into the lymph nodes and direct Ag-specific T cell responses, thus acting as key players in both adaptive and innate immunity. In this study we asked whether IL-27 is produced by human secondary lymphoid organs and what is its functional role on human DCs. To our knowledge, we provide the first evidence that 1) in lymph nodes, macrophages are the major source for IL-27; 2) immature and mature human DCs express functional IL-27R; 3) IL-27 exerts immunosuppressive activity by crippling the Ag processing machinery in immature DCs under steady-state conditions and after pulsing with a viral Ag; and 4) IL-27 is chemotactic for human DCs. Our findings highlight novel mechanisms underlying the immunosuppressive activity of IL-27, suggesting that this cytokine may function as a homeostatic cytokine in secondary lymphoid organs by limiting duration and/or intensity of ongoing adaptive immune responses. The results presented in this study pave the way to future studies aimed at investigating whether dysregulation of IL-27 expression and function may be involved in pathogenesis of autoimmune disease and cancer.

The Immunobiology of Interleukin-27

“…In agreement with this literature, IL-27 has been shown to promote murine DC expression of CD39, which can deplete extracellular ATP and therefore limit inflammasome activation (156). In other studies, the ability of IL-27 to promote human DC expression of PD-L1 provides another mechanism for suppressing T cell activation (157), and there is evidence that IL-27 cripples the ability of DCs to present antigen (158). There have been reports that resting mouse macrophages are not responsive to IL-27 (159), but others have found that IL-27 inhibits the ability of murine macrophages to produce IL-12 and TNF-α (13).…”

Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses

“…Another potential cell candidate is dendritic cells (DCs). Human immature DCs exposed to IL-27 displayed reduced antigen presenting capacity 22 . IL-27 provokes DC derived IL-10, and suppresses downstream Th1 and Th17 response 20, 21 .…”

“…However, the IL-27 receptor complex is also expressed on other immune cell types, including granulocytes 16 and macrophages 17 , indicating that the functional capabilities of IL27 may be even wider and in particular IL27 may play a role in mediating innate immunity. Indeed, IL-27 can impact the function of innate cell subsets, including macrophages 18 , neutrophils 16, 19 , and dendritic cells 20–22 . It has been shown that IL-27 influences innate responses to bacterial challenge in the context of systemic sepsis in genetic manipulation models such as IL-27Rα knock-out murine strains.…”

IL-27: a double agent in the IL-6 family

“…) . While additional investigations are required to explore fully the wider biological functions of IL‐27, emerging data also highlight potential roles for IL‐27 in the control of pain , myeloid cell activation and stromal tissue responses (Fig. ) .…”