Cross-Presentation of Soluble and Cell-Associated Antigen by Murine Hepatocytes Is Enhanced by Collectrin Expression

Abstract

Cross-presentation is a modular series of intracellular events dictating the internalization and subsequent MHC class I (MHC I) display of extracellular Ags. This process has been defined in dendritic cells and plays a fundamental role in the induction of CD8 T cell immunity during viral, intracellular bacterial, and antitumor responses. Herein, acute viral infection of murine liver with adenovirus, a model for intrahepatic cross-presentation, confirms hepatocytes directly contribute to cross-presentation of Ags and priming the pool of naive CD8 T cells within the liver microenvironment. Processing of soluble and cell-associated Ags into peptide displayed by MHC I is however defective in hepatocytes lacking collectrin, an intracellular chaperone protein that localizes within the endoplasmic reticulum-Golgi intermediate compartment. Loss of hepatic collectrin expression leads to the diminished cross-priming and expansion of cytolytic antiviral CD8 T cells. This study demonstrates that collectrin positively regulates processing of engulfed Ags into MHC I:peptide complexes within hepatocytes. Collectrin-mediated cross-presentation supports intrahepatic adaptive antiviral immune responses and may lead to insights into the nature of how the liver acts as a primary site of CD8 T cell activation.

Regulation of the Cell Biology of Antigen Cross-Presentation

“…Liver sinusoidal endothelial cells, Kupffer cells, and hepatocytes also contribute to cross-presentation and expansion of CD8 T cells within the mouse liver during acute adenoviral infection (36). Hepatocyte expression of collectrin, a membrane protein found to promote vesicle fusion during insulin exocytosis by pancreatic β cells (37), has curiously been linked to the expansion of virus-specific CD8 T cells and viral clearance after adenovirus infection (38). Collectrin augmented hepatocyte and not hematopoietic cell cross-presentation and cross-priming of antigen-specific CD8 T cells in vitro in response to either soluble antigen or remnants of infected necrotic hepatocytes (38).…”

“…Hepatocyte expression of collectrin, a membrane protein found to promote vesicle fusion during insulin exocytosis by pancreatic β cells (37), has curiously been linked to the expansion of virus-specific CD8 T cells and viral clearance after adenovirus infection (38). Collectrin augmented hepatocyte and not hematopoietic cell cross-presentation and cross-priming of antigen-specific CD8 T cells in vitro in response to either soluble antigen or remnants of infected necrotic hepatocytes (38). Its role in cross-presentation in these cell types may be related to facilitating vesicular fusion events important for cross-presentation (37, 39).…”

The Contribution of Non-Professional Antigen-Presenting Cells to Immunity and Tolerance in the Liver

“…Indeed, hepatocytes are capable of priming naïve CD8 + T-cells directly and via cross-presentation ( 20 , 45 ) but fail to provide the activated CD8 + T-cells with the necessary survival factor and therefore cause CD8 + T-cell deletion ( 45 , 46 ). A recent study showed that the pathway of antigen processing and loading of MHC-I complex depends on a specific chaperone in the endoplasmatic reticulum–Golgi intermediate compartment called collectrin ( 47 ). This protein is not expressed in KCs or DCs and indicates a distinct mechanism of antigen processing for cross-presentation in hepatocytes ( 47 ).…”

“…A recent study showed that the pathway of antigen processing and loading of MHC-I complex depends on a specific chaperone in the endoplasmatic reticulum–Golgi intermediate compartment called collectrin ( 47 ). This protein is not expressed in KCs or DCs and indicates a distinct mechanism of antigen processing for cross-presentation in hepatocytes ( 47 ).…”

Mechanisms of Immune Tolerance in Liver Transplantation-Crosstalk Between Alloreactive T Cells and Liver Cells With Therapeutic Prospects

“…Paul-Heng et al have found that direct recognition of hepatocyte expressed MHC-I alloantigen (cross presentation) is required for tolerance induction, whereas the indirect recognition of the processed and presented allogeneic peptide on MHC-II by CD4 T cells is not sufficient for tolerance induction although it can prolong the graft survival and generate Tregs to promote transplant tolerance (78, 79). Additionally, processing of the soluble antigens into peptide presented by MHC-I is impaired in hepatocytes lacking collectrin, which is an intracellular chaperone protein within the endoplasmic reticulum-Golgi intermediate compartment and positively regulated (80). Different from other liver cells, hepatocytes can produce exosomes to control the active T cells response and clear the activated T cells through the non-apoptotic way of suicidal emperipolesis (SE), which is a process leading to cell-in-cell structures and promotes cell death through degradation within endosomal/lysosomal compartments (Figure 3) (81, 82).…”