RAGE Ligation Affects T Cell Activation and Controls T Cell Differentiation

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
The Journal of Immunology (Impact Factor: 4.92). 09/2008; 181(6):4272-8. DOI: 10.4049/jimmunol.181.6.4272
Source: PubMed


The pattern recognition receptor, RAGE, has been shown to be involved in adaptive immune responses but its role on the components of these responses is not well understood. We have studied the effects of a small molecule inhibitor of RAGE and the deletion of the receptor (RAGE-/- mice) on T cell responses involved in autoimmunity and allograft rejection. Syngeneic islet graft and islet allograft rejection was reduced in NOD and B6 mice treated with TTP488, a small molecule RAGE inhibitor (p < 0.001). RAGE-/- mice with streptozotocin-induced diabetes showed delayed rejection of islet allografts compared with wild type (WT) mice (p < 0.02). This response in vivo correlated with reduced proliferative responses of RAGE-/- T cells in MLRs and in WT T cells cultured with TTP488. Overall T cell proliferation following activation with anti-CD3 and anti-CD28 mAbs were similar in RAGE-/- and WT cells, but RAGE-/- T cells did not respond to costimulation with anti-CD28 mAb. Furthermore, culture supernatants from cultures with anti-CD3 and anti-CD28 mAbs showed higher levels of IL-10, IL-5, and TNF-alpha with RAGE-/- compared with WT T cells, and WT T cells showed reduced production of IFN-gamma in the presence of TTP488, suggesting that RAGE may be important in the differentiation of T cell subjects. Indeed, by real-time PCR, we found higher levels of RAGE mRNA expression on clonal T cells activated under Th1 differentiating conditions. We conclude that activation of RAGE on T cells is involved in early events that lead to differentiation of Th1(+) T cells.

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    • "The differences between our findings on cytokine production in vivo and in vitro under conditions of T cell skewing may reflect the more complex role of RAGE in T cell activation that manifests as reduced total cytokine production in the setting of antigen exposure in vivo. Indeed, in previous studies, we found reduced proliferative responses of RAGE−/− T cells in mixed lymphocyte reactions as well as reduced proliferative responses of RAGE−/− T cells in vitro[2], [3]. "
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    ABSTRACT: The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA)-induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNγ and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNγ but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA-induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "RAGE is expressed on a variety of cell types including DCs and T cells (Alexiou et al., 2010). Earlier studies on the role of RAGE in T cell activation demonstrated that RAGE blockade (Dumitriu et al., 2005; Moser et al., 2007b) or RAGE deficiency in T cells (Chen et al., 2008; Moser et al., 2007a) resulted in diminished T cell activation and proliferation. Therefore, we considered RAGE to be an attractive candidate receptor for the HMGB1-CD24 complex displayed by the migrant RDCs. "
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    ABSTRACT: The contribution of different DC subsets to effector and memory CD8(+) T cell generation during infection and the mechanism by which DCs controls these fate decisions is unclear. Here we demonstrated that the CD103(+) and CD11b(hi) migratory respiratory DC (RDC) subsets after influenza virus infection activated naive virus-specific CD8(+) T cells differentially. CD103(+) RDCs supported the generation of CD8(+) T effector (Teff) cells, which migrate from lymph nodes to the infected lungs. In contrast, migrant CD11b(hi) RDCs activated CD8(+) T cells characteristic of central memory CD8(+) T (CD8(+) Tcm) cells including retention within the draining lymph nodes. CD103(+) RDCs expressed CD24 at an elevated level, contributing to the propensity of this DC subpopulation to support CD8(+) Teff cell differentiation. Mechanistically, CD24 was shown to regulate CD8(+) T cell activation through HMGB1-mediated engagement of T cell RAGE. Thus, there is distribution of labor among DC subsets in regulating CD8(+) T cell differentiation.
    Preview · Article · Mar 2014 · Immunity
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    • "In macrophages, AGE–RAGE interaction prompts cell chemotaxis and cytokine release via a mechanism involving the activation of NADPH oxidase (Kirstein et al., 1990; Wautier et al., 2001). RAGE also appears to play a role in T lymphocyte activation and differentiation, mediating Th1-type responses such as the synthesis of IFNγ (Chen et al., 2008). Recent work by Akirav et al. (2012) found that RAGE is expressed intracellularly in human T cells following TCR activation but constitutively on T cells from patients with diabetes. "
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    ABSTRACT: A central mechanism driving vascular disease in diabetes is immune cell-mediated inflammation. In diabetes, enhanced oxidation and glycation of macromolecules, such as lipoproteins, insults the endothelium, and activates both innate and adaptive arms of the immune system by generating new antigens for presentation to adaptive immune cells. Chronic inflammation of the endothelium in diabetes leads to continuous infiltration and accumulation of leukocytes at sites of endothelial cell injury. We will describe the central role of the macrophage as a source of signaling molecules and damaging by-products which activate infiltrating lymphocytes in the tissue and contribute to the pro-oxidant and pro-inflammatory microenvironment. An important aspect to be considered is the diabetes-associated defects in the immune system, such as fewer or dysfunctional athero-protective leukocyte subsets in the diabetic lesion compared to non-diabetic lesions. This review will discuss the key pro-inflammatory signaling pathways responsible for leukocyte recruitment and activation in the injured vessel, with particular focus on pro- and anti-inflammatory pathways aberrantly activated or repressed in diabetes. We aim to describe the interaction between advanced glycation end products and their principle receptor RAGE, angiotensin II, and the Ang II type 1 receptor, in addition to reactive oxygen species (ROS) production by NADPH-oxidase enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy. Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets. Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified low-density lipoprotein and pharmacological inhibition of ROS-producing enzymes.
    Full-text · Article · Jun 2013 · Frontiers in Endocrinology
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