Dendritic cell maturation and cross-presentation: timing matters!

Abstract

As a population, dendritic cells (DCs) appear to be the best cross-presenters of internalized antigens on major histocompatibility complex class I molecules in the mouse. To do this, DCs have developed a number of unique and dedicated means to control their endocytic and phagocytic pathways: among them, the capacity to limit acidification of their phagosomes, to prevent proteolytic degradation, to delay fusion of phagosomes to lysosomes, to recruit ER proteins to phagosomes, and to export phagocytosed antigens to the cytosol. The regulation of phagocytic functions, and thereby of antigen processing and presentation by innate signaling, represents a critical level of integration of adaptive and innate immune responses. Understanding how innate signals control antigen cross-presentation is critical to define effective vaccination strategies for CD8(+) T-cell responses.

Keywords: cross-presentation; dendritic cell; dendritic cells maturation; phagocytosis; toll-like receptor.

Figure 1

Schematic representation of the intracellular mechanisms operating throughout the ‘cytosolic’ cross‐presentation pathways (vacuolar pathway not shown). Molecular players (marked with red asterisks) involved in the regulation of these pathways during dendritic cell maturation after toll‐like receptor engagement and the stage (early, mid, or late) at which they act are shown. Exogenous antigens are phagocytosed (1) and partially degraded within the phagosome by lysosomal enzymes (2) that reach the organelle after phagolysosomal fusion, which can be inhibited through lysosomal perinuclear clustering mediated by Rab34. Enzymatic activity of lysosomal enzymes depends on the intraluminal pH which, in turn, is regulated by two systems that are recruited to the phagosomal membrane: vATPase and NOX2. Additionally, lysosomal enzyme expression levels and phagosomal pH are controlled by the transcriptional factor TFEB. After this initial degradation step, the resulting polypeptides are exported to the cytosol (3) by the translocon protein Sec61 and are further processing by the proteasome (4). Peptides are transported to their loading site (5), either the ER (5a) or back to the phagosome (5b). Regardless of the loading site, peptides are trimmed (6) by resident aminopeptidases (IRAP or ERAP) and loaded onto MHC class I molecules (7). In the ER MHC I loading pathway, all participants are present already in the ER, and newly synthesized MHC I molecules are used (7a). On the contrary, in the phagosomal MHC I loading pathway, the loading complex components (including the transporter associated with antigen processing – TAP) are recruited to the phagosome through the interaction between the SNARE Sec22b (resident of the ER‐Golgi intermediate compartment – ERGIC) and syntaxin 4. MHC class I molecules themselves reach the phagosome to be loaded with peptides through SNAP23‐mediated fusion of Rab11a‐positive endosomal recycling compartments (ERC) bringing MHC class I molecules from the cell surface (7b). Finally, MHC class I–peptide complexes are transported to the cell surface where antigen presentation (8) to T cells takes place.