Hepatocytes Express Abundant Surface Class I MHC and Efficiently Use Transporter Associated with Antigen Processing, Tapasin, and Low Molecular Weight Polypeptide Proteasome Subunit Components of Antigen Processing and Presentation Pathway

Abstract

Hepatic expression levels of class I MHC Ags are generally regarded as very low. Because the status of these Ags and their ability to present peptides are important for the understanding of pathogen clearance and tolerogenic properties of the liver, we set out to identify the factors contributing to the reported phenotype. Unexpectedly, we found that the surface densities of Kb and Db on C57BL/6 mouse hepatocytes are nearly as high as on splenocytes, as are the lysate concentrations of mRNA encoding H chain and β2-microglobulin (β2m). In contrast, the components of the peptide-loading pathway are reduced in hepatocytes. Despite the difference in the stoichiometric ratios of H chain/β2m/peptide-loading machineries, both cell types express predominantly thermostable class I and are critically dependent on TAP and tapasin for display of surface Ags. Minor differences in the expression patterns in tapasin−/− background suggest cell specificity in class I assembly. Under immunostimulatory conditions, such as exposure to IFN-γ or Listeria monocytogenes, hepatocytes respond with a vigorous mRNA synthesis of the components of the Ag presentation pathway (up to 10-fold enhancement) but up-regulate H chain and β2m to a lesser degree (<2-fold). This type of response should promote rapid influx of newly generated peptides into the endoplasmic reticulum and preferential presentation of foreign/induced Ag by hepatic class I.

Immunoproteasomes Are Essential for Clearance ofListeria monocytogenesin Nonlymphoid Tissues but Not for Induction of Bacteria-Specific CD8+ T Cells

“…Remarkably, induction of I-proteasomes in nonlymphoid organs, enabled purified hepatocytes to process CD8 ϩ T cell epitopes as efficiently as professional APC from lymphoid tissues. Consequently, our data support the concept that during infection hepatocytes become effective APCs (37). Two mechanisms for enhanced epitope generation could explain this effect: enhanced substrate turnover or altered cleavage site preference.…”

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

“…Based on a large number of immunohistochemical studies in mice and humans, expression of MHC molecules on hepatocytes has been generally regarded as very low. 35,36 However, a recent report 11 has shown that these cells express abundant and conformationally stable MHC class I/peptide complexes with surface densities that are nearly as high as on splenocytes. Using quantitative flow cytometry techniques and calibration standards to adjust for the differences in cell size and autofluorescence between hepatocytes and splenocytes, it was demonstrated that, on a per cell basis, mouse hepatocytes express 7-to 16-fold higher levels of MHC class I molecules than splenocytes, whereas membrane densities were at least 30% to 75% as high as those estimated on splenic lymphocytes.…”

“…Using quantitative flow cytometry techniques and calibration standards to adjust for the differences in cell size and autofluorescence between hepatocytes and splenocytes, it was demonstrated that, on a per cell basis, mouse hepatocytes express 7-to 16-fold higher levels of MHC class I molecules than splenocytes, whereas membrane densities were at least 30% to 75% as high as those estimated on splenic lymphocytes. 11 Expression of both ICAM-1 and MHC class I is normally polarized. Consequently, it is likely that local densities of these molecules are higher at the basolateral surface of hepatocytes.…”

“…9 Within the liver, there is increasing evidence that hepatocytes may function as APCs, a finding highly relevant to some hepatotropic viral infections such as those by the hepatitis C virus. Hepatocytes express high levels of major histocompatibility complex (MHC) Class I molecules, 11 as well as intercellular adhesion molecule-1 (ICAM-1) and CD1d, 12-14 a ligand recognized by NKT lymphocytes. 15 These cells are therefore fully competent to interact and activate lymphocytes via MHC class I receptors.…”

In vivo delivery of a microRNA-regulated transgene induces antigen-specific regulatory T cells and promotes immunologic tolerance

“…Twelve days postvaccination in vivo antigen-specific cytolytic activity was evaluated cotransferring the following: 5 ϫ 10 6 5-(and 6-)carboxyfluorescein diacetate succinimidyl ester (CFSE) hi (2.5M; Molecular Probes) GFP [200][201][202][203][204][205][206][207][208] pulsed, 5 ϫ 10 6 CFSE int (250nM) hepatitis B virus envelope small subunit immunodominant epitope (HBs) [28][29][30][31][32][33][34][35][36][37][38][39] pulsed, and 5 ϫ 10 6 CFSE low (25nM) unpulsed per mouse. Eighteen hours later, single-cell suspension was prepared from lymph nodes draining the site of vaccination.…”