Page 119 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 6 Overview of T-Cell Recognition 103

encounter, for example, skin, mucosae, and lungs. Here, they are through recognition of the target cell synthesizing the viral or
able to receive molecular signals from pathogens that both activate tumor antigen. This cytosolic cross-presenting route requires that
the DCs and promote internalization and processing of antigens. internalized or phagocytosed proteins from pathogen-infected
These pathogen-derived signals initiate DC mobilization, exit or transformed cells gain access to the cytosol. A mechanism
from the tissue, and transit to secondary lymphoid organs. Other that allows transport of an intact or partially unfolded/degraded
subsets of DCs are resident cells within the lymph node and protein from the lumen of lysosomal compartments into the
encounter antigens delivered either via the lymphatics or by cytosol is therefore needed. Export has been speculated to involve
other cell types that transit from the site of antigen encounter a transmembrane channel or a direct extraction mechanism.
to the lymphoid tissue. Proteins, such as those involved in ER-associated degradation
DCs gain access to secondary lymphoid tissue through expres- (ERAD), have been implicated by many studies, as has the Sec61
sion of chemokine receptors and become localized to regions translocon. Cross-presentation has also been shown to require
that allow encounter with recirculating T cells that enter the an endosomal, pH-dependent reductase (GILT), suggesting that
lymphoid tissue to survey potential antigen-bearing cells. DCs protein unfolding may be needed for antigenic protein transfer.
also express key costimulatory molecules, such as CD80 and After crossing the lysosomal membrane, the cytosolically
CD86, and cytokines, such as IL-12, which are essential to prime localized proteins can now enter the classical or endogenous
naïve T cells for expansion and differentiation into the effector pathway of class I–restricted presentation: proteolysis by the
cells (Chapter 12). proteasome, import of the derived peptides into the ER via TAP,
The intracellular events associated with antigen acquisition and peptide binding being facilitated/edited by the components
and presentation by DCs is easy to envision for CD4 T cells of PLC. The peptide class I complex would then be exported
because the antigens that need to access class II molecules can from the ER to the cell surface via the typical default secretory
become internalized into the key endosomal compartments. For pathway (Fig. 6.9).
MHC class I–restricted antigen presentation, particularly for The vacuolar pathway provides as an alternative means for
responses to pathogens that do not infect DCs or become systemic, cross-presentation. In this pathway, the internalized pathogen
and for responses to tumors that are sequestered in distant sites or tumor-derived proteins remain in the endosomal compart-
in the body, this exogenous presentation poses a challenge because ments, where they are degraded by lysosomal proteases. Class I
the site of peptide binding to class I is in the ER, generally not molecules at the cell surface then encounter the antigens during
thought to be readily accessible to internalized proteins. internalization and recycling. Some evidence also suggests
In the last decades, an auxiliary pathway of antigen presenta- that components of the ER-associated PLC may localize to the
tion, termed cross-presentation, has been discovered. This antigen endosomal compartments and intersect with MHC class I,
presentation event for CD8 T-cell priming to exogenous antigens allowing assembly of the complex within these compartments
involves uptake and class I–restricted presentation of cell- by a similar mechanism as in the ER. Under what conditions,
associated antigens from tumors or virus-infected cells, and those within what cells in vivo, and with what antigens these two
associated with intracellular bacteria pathogens, such as listeria potential pathways of exogenous presentation are operational
or fungal pathogens whose proteins are not synthesized within remain to be defined.
the APC. Cross-presentation also serves to prime CD8 T cells Both pathways of cross-presentation require that the internal-
reactive with pathogen-derived proteins and aggregates released ized antigen be protected from rapid and terminal degradation.
by infected cells in distal sites, such as the respiratory tract. 37,38 Alkalization of the compartment diminishes recruitment of
Internalization of cell- or pathogen-associated antigens into enzymes responsible for acidification of lysosomal compart-
endosomal/lysosomal compartments through phagocytosis or ments, such as nicotinamide adenine dinucleotide phosphate
receptor-mediated uptake initiates cross-presentation and ulti- (NADPH) oxidase 2 (NOX-2). Most of the lysosomal enzymes
mately leads cell-surface presentation of the pathogen-derived are pH dependent and require acidic pH for optimal activity.
peptides in association with class I molecules, leading to CD8 Strategies to modify this acidification, either by genetic means
T-cell activation, cell division, and differentiation. These primed or by pharmacological approaches, have been shown to promote
CD8 T cells ultimately become programmed to deliver their cross-presentation.
effector function, most commonly cytolysis, on either pathogen-
infected cells or transformed cells, eliminating them from the host. THE MHC-PRESENTED PEPTIDOME
The intervening, intracellular events involved in cross-
presentation are the subject of active research. Early studies Isolation and sequencing of host peptides constitutively bound
pointed to the possibility that this presentation occurs in only and presented by MHC molecules has yielded significant new
a subset of DCs, now known to be distinguished by markers, insight regarding the diversity, abundance, and source of peptides
+
+
such as CD8α in mice and BDCA3 cells in humans. Ablation that are normally displayed. 39,40 The key technical advance was
of DCs in vivo eliminates cross-presentation of pathogen- the development and use of tandem mass spectroscopy to
41
associated antigens, emphasizing the need for this cell type for sequence very low abundance peptides. In this approach, MHC
efficient cross-priming. class I or class II molecules of interest are isolated by antibody
There are a number of studies that suggest that cross- affinity chromatography. The bound peptides are then eluted,
presentation is dependent on TAP and the proteasome because and the low-molecular-weight material, including peptides, are
in many cases, presentation of the epitope is sensitive to inhibi- separated from antibody and class I and then subjected to
tors of these proteins. Because of the shared cellular cofactors sequencing.
involved in peptide generation and loading, it is envisioned From these studies, it is now estimated that as many as 10,000
that the same peptides would be presented by the endogenous different self peptides are in association with a given class II
and the cross-presentation route. This conclusion would seem molecule on the cell surface. For human APCs that can express
to be most beneficial to effective surveillance and protection 6–10 different class II species (HLA-DR, HLA-DQ, and HLA-DP