Cross‐presentation: underlying mechanisms and role in immune surveillance

Abstract

It was originally thought that a cell's major histocompatibility complex (MHC) class I molecules presented peptides derived exclusively from proteins synthesized by the cell itself. However, in some circumstances, antigens from the extracellular environment can be presented on MHC class I molecules and stimulate CD8(+) T-cell immunity, a process termed cross-presentation. Cross-presentation was originally discovered as an obscure phenomenon in transplantation immunity. However, it is now clear that it is a major mechanism by which the immune system monitors tissues and phagocytes for the presence of foreign antigen. Cross-presentation is the only pathway by which the immune system can detect and respond to viral infections or mutations that exclusively occur in parenchymal cells rather than in bone marrow-derived antigen-presenting cells (APCs). Professional APCs, such as dendritic cells, are the principal cells endowed with the capacity to cross-present antigens. In this process, the APCs acquire proteins from other tissue cells through endocytic mechanisms, especially phagocytosis or macropinocytosis. The internalized antigen can then be processed through at least two different mechanisms. In one pathway, the antigen is transferred from the phagosome into the cytosol, where it is hydrolyzed by proteasomes into oligopeptides that are then transported by the transporter associated with antigen processing to MHC class I molecules in the endoplasmic reticulum or phagosomes. In a second pathway, the antigen is cleaved into peptides by endosomal proteases, particularly cathepsin S, and bound by class I molecules probably in the endocytic compartment itself. Depending on the nature of the antigen, one or both of these pathways can contribute to cross-presentation in vivo. The outcome of cross-presentation can be either tolerance or immunity. Which of these outcomes occurs is thought to depend on whether antigens are acquired by themselves alone, leading to tolerance, or with immunostimulatory signals, leading to immunity. One source of such signals is from dying cells that release immunostimulatory 'danger' signals that promote the generation of immunity to their cellular antigens. In addition to the critical role of cross-presentation in normal immune physiology, this pathway has considerable potential for being exploited for developing subunit vaccines that elicit both CD4(+) and CD8(+) T-cell immunity.

Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation

“…It is noteworthy that proper expression and presentation of the encoded antigen requires the escape of RNA from the macropinosomes. Even though endosomal compartments appear to be leaky or possess channels or transporters facilitating the egression and cross presentation of antigens from endosomes [26][27][28][29][30] the penetration mechanisms of RNA through the endocytic membrane remain to be investigated.…”

In vivo Colocalization of Antigen and CpG within Dendritic Cells Is Associated with the Efficacy of Cancer Immunotherapy

“…The priming of CTL depends on the unique feature of DCs to present captured antigens on MHC class I, a process known as cross-presentation (26). We next tested the crosspresenting abilities of lymph node DCs directly ex vivo on coculture with B3Z cells.…”

Biomarkers for the Development of Cancer Vaccines

“…As part of the activation of CD8 CTL, antigens are broken down from their constituent proteins to peptides [12]. Therefore, it follows that vaccination of patients using peptides derived from prostate antigens may lead to the beneficial generation of protective immunity.…”