Abstract
Efficient immune responses require regulated antigen presentation to CD4 T cells. IL-10 inhibits the ability of dendritic cells (DCs) and macrophages to stimulate antigen-specific CD4 T cells; however, the mechanisms by which IL-10 suppresses antigen presentation remain poorly understood. We now report that IL-10 stimulates expression of the E3 ubiquitin ligase March-I in activated macrophages, thereby down-regulating MHC-II, CD86, and antigen presentation to CD4 T cells. By contrast, IL-10 does not stimulate March-I expression in DCs, does not suppress MHC-II or CD86 expression on either resting or activated DCs, and does not affect antigen presentation by activated DCs. IL-10 does, however, inhibit the process of DC activation itself, thereby reducing the efficiency of antigen presentation in a March-I-independent manner. Thus, IL-10 suppression of antigen presenting cell function in macrophages is March-I-dependent, whereas in DCs, suppression is March- I-independent.
Highlights
IL-10 suppresses antigen presentation by macrophages (M⌽) and dendritic cells (DCs)
IL-10 Reduces MHC-II and CD86 Expression on Activated M⌽—To begin to examine the mechanism(s) by which IL-10 suppressed the ability of M⌽ to activate CD4 T cells, bone marrow-derived M⌽ were activated by treatment with IFN-␥ for 24 h and cultured alone or with IL-10 for an additional 18 h
The anti-inflammatory cytokine IL-10 suppresses the ability of DCs, monocytes, and M⌽ to stimulate antigen-specific CD4 T cells [14]; precisely how IL-10 suppresses various aspects of antigen-presenting cells (APCs) function remains to be determined
Summary
IL-10 suppresses antigen presentation by macrophages (M⌽) and dendritic cells (DCs). Results: IL-10 promotes expression of the MHC class II and CD86 E3 ubiquitin ligase March-I and suppresses antigen presentation in activated M⌽ but not in DCs. IL-10 suppression of antigen presenting cell function in macrophages is March-I-dependent, whereas in DCs, suppression is MarchI-independent. Pathogen-specific CD4 T cells can be stimulated by a variety of antigen-presenting cells (APCs) that express MHC class II molecules (MHC-II) and co-stimulatory proteins including CD80, CD86, and CD40 [1]. MHC-II is constitutively expressed in DCs, and exposure of DCs to pathogens stimulates TLR signaling pathways that “activate” DCs to expresses large amounts of surface peptide1⁄7MHC-II complexes (pMHC-II) and co-stimulatory proteins essential for antigen-specific naive CD4 T cell activation [2, 3]. Enhanced expression of MHC-II and co-stimulatory molecules promotes the ability of APCs to stimulate CD4 T cells, whereas reduced expression of these proteins on the surface of these cells suppresses this function. IL-10 suppresses APC function in M⌽ and DCs by distinct March-I-dependent and March-I-independent mechanisms
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