Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Abstract

Dendritic cells (DCs) are among the first professional APCs encountered by the obligate intracellular bacterium Chlamydia during infection. Using an established mouse bone marrow–derived DC line, we show that DCs control chlamydial infection in multiple small inclusions characterized by restricted bacterial growth, impaired cytosolic export of the virulence factor chlamydial protease–like activity factor, and interaction with guanylate-binding protein 1, a host cell factor involved in the initiation of autophagy. During maturation of infected DCs, chlamydial inclusions disintegrate, likely because they lack chlamydial protease–like activity factor–mediated protection. Released cytosolic Chlamydia are taken up by autophagosomes and colocalize with cathepsin-positive amphisomal vacuoles, to which peptide transporter TAP and upregulated MHC class I (MHC I) are recruited. Chlamydial Ags are subsequently generated through routes involving preprocessing in amphisomes via cathepsins and entry into the cytosol for further processing by the proteasome. Finally, bacterial peptides are reimported into the endosomal pathway for loading onto recycling MHC I. Thus, we unravel a novel pathway of MHC I–mediated cross-presentation that is initiated with a host cellular attack physically disrupting the parasitophorous vacuole, involves autophagy to collect cytosolic organisms into autophagosomes, and concludes with complex multistep antigenic processing in separate cellular compartments.

Nucleotide-dependent farnesyl switch orchestrates polymerization and membrane binding of human guanylate-binding protein 1

“…Overexpression of marker proteins such as Rab5, Rab7, or Rab9 enhanced this colocalization. Other groups have already identified certain GBPs on phagocytosed latex bead (42,43) and bacteria (44,45). In some cases, we observed recruitment of hGBP1 very early during formation of phagocytic cups.…”

Chlamydia trachomatis-Infected Epithelial Cells and Fibroblasts Retain the Ability To Express Surface-Presented Major Histocompatibility Complex Class I Molecules

“…The MHC I antigen presentation pathway enables the immune system to detect infected cells displaying peptides from foreign proteins. Studies using mouse models have underscored the role of the CD8 ϩ T cell response in the recognition of Chlamydiainfected cells (8). Thus, tight control of MHC I expression and surface presentation is essential for the outcome of a successful and efficient immune response to the pathogens.…”

Immunologic manifestations of autophagy

“…In the context of autoimmunity, autophagy may promote presentation of citrullinated antigens (85). Less is understood regarding how autophagy affects MHC class I presentation, although effects have been noted (86). Thus, autophagy affects antigen presentation in a variety of contexts.…”