Abstract
Major histocompatibility complex class I (MHC I) on antigen presenting cells (APCs) is a potent molecule to activate CD8+ T cells and initiate immunity. P2X7 receptors (P2X7Rs) are present on the plasma membrane of APCs to sense the extracellular danger signal adenosine-5′-triphosphate (ATP). P2X7R activates the inflammasome and the release of IL-1β in macrophages and other immune cells to initiate the inflammatory response. Here we show that P2X7R stimulation by ATP in APCs decreased the amount of MHC I at the plasma membrane. Specific antagonism or genetic ablation of P2X7R inhibited the effects of ATP on levels of cellular MHC I. Furthermore, P2X7R stimulation was able to inhibit activation of CD8+ T cells via specific MHC I-oligopeptide complexes. Our study suggests that P2X7R activation on APCs is a novel inhibitor of adaptive CD8+ T cell immunity.
Highlights
Adaptive immunity requires the activation of T lymphocytes by antigen presenting cells (APCs), which present antigen bound to major histocompatibility complex (MHC) molecules
We found that ATP treatment of macrophages resulted in a significant decrease of the mean fluorescent intensity (MFI) of extracellular membrane MHC class I (MHC I) staining measured by flow cytometry
We found that P2X7 receptors (P2X7Rs) stimulation in APCs reduces cellular and surface MHC I levels, with the consequence to impair peptide presentation and activation of CD8+ T cells through MHC class I molecules
Summary
Adaptive immunity requires the activation of T lymphocytes by antigen presenting cells (APCs), which present antigen bound to major histocompatibility complex (MHC) molecules. Macrophages are important APCs, since they are ubiquitously localized through the body and initiate the immune response against pathogen by the production of cytokines and by their phagocytic, cytotoxic, and antigen-presenting capabilities [1]. Intracellular antigens are presented by MHC class I (MHC I) molecules and activate cytotoxic CD8+ T cells, extracellular antigens are presented by MHC class II (MHC II) molecules to activate CD4+ T helper cells [3,4]. A mechanism termed cross-presentation permits some extracellular antigen to stimulate CD8+ T cells via the MHC I pathway of APCs [5,6]. MHC I molecules that do not fold properly or which lack antigen peptide, are retro-translocated into the cytosol and degraded by the proteasome [9]
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