RAGE Expression in Human T Cells: A Link between Environmental Factors and Adaptive Immune Responses

Abstract

The Receptor for Advanced Glycation Endproducts (RAGE) is a scavenger ligand that binds glycated endproducts as well as molecules released during cell death such as S100b and HMGB1. RAGE is expressed on antigen presenting cells where it may participate in activation of innate immune responses but its role in adaptive human immune responses has not been described. We have found that RAGE is expressed intracellularly in human T cells following TCR activation but constitutively on T cells from patients with diabetes. The levels of RAGE on T cells from patients with diabetes are not related to the level of glucose control. It co-localizes to the endosomes. Its expression increases in activated T cells from healthy control subjects but bystander cells also express RAGE after stimulation of the antigen specific T cells. RAGE ligands enhance RAGE expression. In patients with T1D, the level of RAGE expression decreases with T cell activation. RAGE+ T cells express higher levels of IL-17A, CD107a, and IL-5 than RAGE− cells from the same individual with T1D. Our studies have identified the expression of RAGE on adaptive immune cells and a role for this receptor and its ligands in modulating human immune responses.

Tax is Involved in Up-regulation of HMGB1 Expression Levels by Interaction with C/EBP

“…Generally, HMGB1 is expressed at a basal level as an architectural chromatin-binding protein, but at a slightly elevated level via passive release from damaged or necrotic cells (Beyer et al, 2012;Yi et al, 2013) or active secretion (Akirav et al, 2012;Kang et al, 2013;Mohammad et al, 2013). Moreover, overexpression of HMGB1 protein is observed in breast, colon, and gastrointestinal cancers, as well as in leukemia and other diseases (Kostova et al, 2010;Ohmori et al, 2011;Jube et al, 2012;Lee et al, 2012;Liu et al, 2012;Xing et al, 2012;Yu et al, 2012;Stoetzer et al, 2013).…”

“…In the nucleus, HMGB1 functions as a non-histone nucleosomal protein that binds DNA, contributes to stabilization of nucleosomes, and promotes DNA repair and replication (Bustin, 1999). In the extracellular milieu, HMGB1 is a pro-inflammatory cytokine that acts as an alarmin via passive release from damaged or necrotic cells (Beyer et al, 2012;He et al, 2012;Yi et al, 2013) or by active secretion from innate immune system cells in response to LPS, TNF-a or IL-1β stimulation to induce T-cell activation, cytokine production, and inflammatory responses by the transduction of cellular signals through its receptors (Akirav et al, 2012;Kang et al, 2013;Mohammad et al, 2013). Aside from these pro-inflammatory functions, HMGB1 protein also promotes regeneration processes and accelerates cell cycle progression.…”

Deletion of Receptor for Advanced Glycation End Products Exacerbates Lymphoproliferative Syndrome and Lupus Nephritis in B6-MRL Fas lpr/j Mice

“…Further studies will be needed to confirm this hypothesis. RAGE is found on cytoplasmic membrane of murine T lymphocytes and in the cytosol of human T cells and is upregulated after the stimulation of these cells (35). However, its functions have not been extensively studied.…”

Potential markers for early diagnostics of Colorectal cancer and Inflammatory bowel disease in humans : intestinal microorganisms and immune system (teammates or rivals)

“…Interestingly, the important mentioned ligand HMGB-1 is also a ligand for Toll-like receptor (TLR)-4 involved in some inflammatory responses [31]. Signaling through RAGE induces intracellular intermediaries including NF-κB, Mitogen-activated protein kinases (MAPK), PI3K/Akt, Rho GTPases, Jak/STAT and Src family kinases [32]. The increased expression of RAGE, as well as its frequent relation with HMGB-1 expression under condition of tissue stress, makes these two molecules suitable as putative new markers for early diagnosis of mucosa alterations together with the stroma architecture imaging.…”