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

Abstract

During infection, TLR agonists are released and trigger mature as well as differentiating innate immune cells. Early encounter with TLR agonists (R848; LPS) blocks conventional differentiation of CD14 1 monocytes into immature dendritic cells (iDCs) resulting in a deviated phenotype. We and others characterized these APCs (TLR-APC) by a retained expression of CD14 and a lack of CD1a. Here, we show in addition, expression of programmed death ligand-1 (PD-L1). TLR-APCs failed to induce T-cell proliferation and furthermore were able to induce CD25 1 Foxp3 1 T regulatory cells (Tregs). Since PD-L1 is described as a key negative regulator and inducer of tolerance, we further analyzed its regulation. PD-L1 expression was regulated in a MAPK/cytokine/STAT-3-dependent manner: high levels of IL-6 and IL-10 that signal via STAT-3 were produced by TLR-APCs. Blocking of STAT-3 activation prevented PD-L1 expression. Moreover, chromatin immunoprecipitation revealed direct binding of STAT-3 to the PD-L1 promoter. Those findings indicate a pivotal role of STAT-3 in regulating PD-L1 expression. MAPKs were indirectly engaged, as blocking of p38 and p44/42 MAPKs decreased IL-6 and IL-10 thus reducing STAT-3 activation and subsequent PD-L1 expression. Hence, during DC differentiation TLR agonists induce a STAT-3-mediated expression of PD-L1 and favor the development of tolerogenic APCs.Keywords: DC . PD-L1 . STAT-3 . Tolerance . TLR See accompanying Commentary by Sumpter and ThomsonSupporting Information available online IntroductionDC are initiators and modulators of the adaptive immune response [1]. They are able to induce T-cell activation as well as T-cell tolerance. During infection, DCs are confronted with pathogen-associated molecular patterns (PAMP), which in turn trigger effector functions in innate immune cells. For example, immature DCs (iDCs) generated from monocytes by in vitro culture with GM-CSF and IL-4 (G4) mature and become fully activated upon stimulation with TLR agonists. Mature DCs (mDCs) in turn activate most efficiently naïve T cells [2]. However, during infection induction of inhibitory immune pathways can also be observed [3,4]. Here, we investigate an alternative TLR-induced APC phenotype, which inhibits immune reactivity. It has been shown that encounter of monocytes with LPS during the very beginning of the differentiation process blocks conventional differentiation to iDCs. A phenotypically distinct APC type (TLR-APC) is generated, characterized by a [5][6][7]. Activation of p38 MAPK, the secretion of IL-10 and the inactivation of ERK and NF-kB [7] have been correlated with the generation of TLR-APCs. LPS-treated cells showed in addition an intense STAT-3 phosphorylation. Differentiation processes of DCs are plastic and can be influenced by various factors, e.g. cytokines. Many cytokines mediate their cellular response via the JAK/STAT signaling pathway thereby controlling the status of transcription and cellular differentiation. For instance, during the maturation of DCs, a switch occurs from constit...

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