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.
Highlights
Adaptive T cell responses are modified by T cell activation signals delivered through the T cell receptor (TCR) and costimulatory ligands, as well as environmental factors [1,2]
We have found Receptor for Advanced Glycation Endproducts (RAGE) expression in human T cells after activation in healthy control subjects and under resting conditions in patients with diabetes
In which RAGE is expressed on the cell surface and in granules, RAGE expression in T cells was intracellular and colocalized with endosomes
Summary
Adaptive T cell responses are modified by T cell activation signals delivered through the T cell receptor (TCR) and costimulatory ligands, as well as environmental factors [1,2]. The effects of cytokines on T cell differentiation have been appreciated for many years, but nutrients including glucose, metabolites, and other molecules such as products of cell death may affect the activation signals and transcriptional machinery that control cell differentiation [3,4]. These factors, which serve as modulators rather than primary initiators of immune responses, have not been well studied; in part because their role may be defined by the setting of the immune responses in vivo which is difficult to recreate in vitro. The importance of hyperglycemia, following destruction of b cells may be reflected by the more rapid decline in b cell function in T1D after the onset of hyperglycemia compared to prior to hyperglycemia, and the amelioration of b cell decline with tight glycemic control in the Diabetes Control and Complications Trial [7]
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