ERK/p38 MAP‐kinases and PI3K are involved in the differential regulation of B7‐H1 expression in DC subsets

Abstract

Regulatory molecules of the B7-H-family expressed by DC are important for immune homeostasis, but their regulation is largely unknown. When investigating the pathways regulating B7-H1 expression in monocyte-derived DC (MoDC), freshly isolated myeloid DC (mDC) and plasmacytoid DC, respectively, we showed that in MoDC and mDC B7-H1 expression was upregulated by a standard cytokine cocktail, poly I:C or LPS. MoDC utilize ERK and PI3K pathways to upregulate B7-H1 in response to cytokines, whereas p38 kinase was predominantly utilized in response to poly I:C. In mDC, ERK and p38 pathways are involved in B7-H1 regulation, and similar to MoDC, mainly p38 signaling was required for poly I:C-induced expression of B7-H1. Plasmacytoid DC responded only to CpG with upregulation of B7-H1 and in addition to p38 also utilized the PI3K and ERK pathways to regulate B7-H1 expression. As a functional consequence of B7-H1 expression on DC, we demonstrate downmodulation of IFN-c production in T cells. Thus, the differential regulation of B7-H1 on DC subsets may suppress immune responses variably, depending on the target DC population. Further analysis of the regulatory mechanisms may facilitate the development of new immunosuppressive therapies, utilizing the regulation of B7-H1 expression on DC.Key words: B7-H1 regulatory molecules . Dendritic cells . Signal transduction Supporting Information available online IntroductionMechanisms that limit undesirable T-cell activation are important for the maintenance of peripheral tolerance. In particular, the expression of positive or negative regulatory molecules on APC is crucial. In humans, the most potent type of APC are DC, which consist of myeloid and plasmacytoid subpopulations as well as Langerhans cells. Although originally defined by their potent T-cell activation capacity, DC are obviously also involved in the maintenance of peripheral tolerance and immune homeostasis, as several types of tolerogenic DC have been described [1,2].To provide signals for the induction of T-cell immunity, DC must be matured and activated with microbial agents or cytokines, among others, in order to become equipped with an appropriate set of costimulatory molecules [3]. In contrast, immature DC lack cytokine production and surface expression of several T-cell costimulatory molecules and, Ã These authors contributed equally to this work. hence, have been shown to tolerize T cells or to induce regulatory T cells [4,5].In addition, DC can also express T-cell regulatory molecules that limit immune responses and protect the body from overwhelming injury. One recently identified molecule, B7-H1 (CD274, PD-L1-programmed death receptor ligand 1), has been implicated in the downregulation of immune responses in different human diseases, such as hepatitis, chronic gastritis, renal inflammatory disease, autoimmunity and different types of cancer [6][7][8][9][10][11][12].B7-H1 is a type 1 transmembrane glycoprotein and a member of the B7 superfamily and one of two ligands for the CD28 homologue programmed death-1...

IL-12 Regulates B7-H1 Expression in Ovarian Cancer-associated Macrophages by Effects on NF-κB Signalling

“…While blocking ERK pathway can restore sensitivity of T24 cells to CTL-mediated killing by downregulation B7-H1 expression . In DC subsets, ERK/p38 MAP-kinases and PI3K were involved in the differential regulation of B7-H1 expression (Karakhanova et al, 2010). Our research illustrated that IL-12 regulated B7-H1 expression via NF-κB signaling pathway in monocytederived macrophages.…”

Immunoregulatory Molecule B7-H1 (CD274) Contributes to Skin Carcinogenesis

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PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3

“…So far, no general pathway is known which controls PD-L1 expression. Depending on stimulus and cell type, the expression of PD-L1 was found to correlate with various signaling molecules: p44/42 and/or p38 MAPKs [26,27] or STAT-1, STAT-3 and IRF-1 [28][29][30].…”

“…So far, no general pathway is known which controls PD-L1 expression. Depending on stimulus and cell type, the expression of PD-L1 was found to correlate with various signaling molecules: p44/42 and/or p38 MAPKs [26,27] or STAT-1, .Here, we characterize the phenotype and function of APCs induced by an early TLR-mediated block of conventional differentiation of iDC. These TLR-APCs had a tolerogenic phenotype and could be induced by different classes of TLR-agonists (TLR7/8 R848 and TLR4 LPS).…”