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252 Part III Immunologic Basis of Hematology

such antigens in the form of apoptotic cells, apoptotic microparticles, organs, where actual presentation occurs. mDCs display higher levels
necrotic cells, antibody-opsonized cells, immune complexes, and HSPs of proteolysis than imDCs do, allowing appropriate degradation of
(intracellular chaperones for antigenic peptides, which are released by the antigens for loading onto MHC molecules. These differences
necrotic cells). 55,56 DCs even acquire antigens via phagocytosis of are accounted for by several features unique to DCs, such as low
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particles released from intracellular vesicles (referred to as exosomes). levels of lysosomal proteases in immature stages compared with
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Finally, DCs may even nibble bits of live cells to acquire antigens. macrophages, expression of protease inhibitors (cystatin C), regula-
This phenomenon of cross-presentation is especially efficient in, if tion of lysosomal pH (and hence activity of proteases) by regulation
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not unique to, DCs compared with other APCs. Evaluation of freshly of the acidifying V-type H -ATPase activity, and consumption of
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isolated lymphoid organ-resident human DCs has confirmed that H upon reaction with superoxide radicals generated by NADPH
these cells also have the capacity to cross-present soluble antigens (nicotinamide adenine dinucleotide phosphate) oxidase NOX2 in
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similarly to their blood counterparts. 59 maturing DCs. During maturation, trafficking of MHC class II
Mechanistically, cross-presentation occurs via two major pathways: molecules to the surface is dramatically increased, probably because
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the cytosolic and the vacuolar pathways. In the first, antigens are of degradation of Ii chain (containing endosome-lysosome target-
transferred to the cytoplasm, which is followed by processing by the ing signal) in acidic compartments, leading to transport of MHC
proteasome and loading onto newly formed MHC class I molecules class II molecules via the constitutive secretory pathway to the cell
(phagosome-to-cytosol pathway), with a possible recruitment of the membrane.
ER machinery for antigen processing and MHC class I loading (see In addition to direct presentation of intracellular antigens and
Fig. 23.2). 61–64 This pathway is sensitive to proteasome inhibitors, cross-presentation of internalized material, DCs can acquire pre-
suggesting that proteins access the cytosol and are degraded by formed MHC class I molecules in complex with antigens from other
proteasomes, but whether the peptide loading occurs via the classical cells by the process of trogocytosis (transfer of cell-membrane patches
MHC I pathway or in endocytic compartments remains to be deter- or individual proteins between cells) or through gap junctions, in a
mined. 64,65 The vacuolar pathway is resistant to proteasome inhibitors process termed cross-dressing; this allows rapid presentation without
and sensitive to inhibitors of lysosomal proteolysis, and it is known to processing of antigens. It has been suggested that memory CD8
be cathepsin S–dependent, thus indicating that both antigen process- T cells are preferentially activated by this mode of presentation in
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ing and loading onto MHC class I molecules may occur in endocytic contrast to naive T cells. It further provides a mechanism for antigen
compartments (see Fig. 23.2). 66,67 The relative contribution of the transfer between DC populations, which can be exploited for vaccine
cytosolic and vacuolar pathways is still unclear, but some evidence design. Thus it has been shown that ex vivo loaded DCs sometimes
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suggests the predominant use of the cytosolic pathway. Currently, do not directly activate host CD8 T cells, which rather requires
it is known that specific DC subsets are more efficient at cross- transfer of peptide–MHC complexes from vaccine DCs to resident
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presentation, with the resident CD8α and the migratory CD1013 DCs for efficient priming. 80
DCs being the most efficient. 68,69 In humans, the proposed CD8α
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homologue cells—the CD141 (BDCA3 ) DCs—are specialized at
cross-presentation. 70–73 Finally, in recent years, it has been described T-CELL ACTIVATION
that TLR signaling can influence the maturation of phagosomes and
also can have an effect on the accumulation of MHC class I molecules T-cell activation systematically requires three signals. Signal 1
in the phagosomes for cross-presentation. 74 is generated by the T-cell receptor (TCR) after engagement by a
peptide–MHC complex on the APC. Signal 2, or costimulatory
Major Histocompatibility Class II Antigen Presentation signal, determines qualitative and quantitative elements of T-cell acti-
vation and differentiation and is required for priming of naive T cells.
(Exogenous Route) Signal 3 specifies the type of response to be mounted, inducing either
Th1 or Th2 differentiation in CD4 T cells or promoting a regulatory
Assembly of MHC class II molecules, which present antigen in the phenotype. MHC–peptide complexes, costimulatory molecules, and
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form of short peptides to CD4 T lymphocytes, occurs in the ER other signaling and adhesion molecules promote DC contact with T
of DCs. After being assembled, these MHC class II molecules are cells via formation of an immunologic synapse that determines the
transported to specialized compartments in the lysosomal system duration and strength of signals transduced to T cells, leading to their
involved in the processing of exogenous antigens. These include subsequent activation. The minimum time for productive interaction
MIIVs, which are protease-rich compartments containing newly between naive T cells and DCs is 6 to 30 hours, with shorter time
synthesized MHC class II molecules. Epidermal DCs or Langerhans periods required for memory T-cell activation. 81,82 Although only a
cells contain cytoplasmic tubules with internal striations called few peptide–MHC complexes (<10) are sufficient to trigger calcium
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Birbeck granules. Birbeck granules are rich in langerin (CD205), fluxes in T cells, only mDCs can prime naive CD4 and CD8 T
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a C-type lectin necessary for granule formation and possibly for cells. Remarkably, relatively few peptide–MHC complexes (<200)
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capture of pathogens. After being endocytosed by imDCs, antigens are necessary on mDCs to activate T cells. Compared with other
are partially retained within lysosomes. Upon receiving a maturation APCs, such as B cells and monocytes, DCs are up to 1000-fold more
signal, the pH of lysosomes decreases to less than 5 (owing to the efficient at activating T cells. 85
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activation of a vacuolar H -ATPase). Concomitantly, there is antigen Costimulatory molecules include the CD80 and CD86 members
degradation caused by activation of proteases such as cathepsins. of the B7 family, which ligate to CD28 on T cells, and members of
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Cystatin C, a protein that blocks the activity of cathepsin S, is also the TNF family, such as CD40 (Table 23.4). Notably, one new
degraded, thereby allowing the degradation of invariant chain peptide member of the B7 family, B7-DC, is unique to DCs and stimulates
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(Ii chain), which normally blocks access of antigenic peptides to naive T cells highly efficiently. Other molecules play inhibitory
MHC class II molecules. These changes occur in late endosomes roles upon encountering their receptor on T cells. For example,
and lysosomes (the MIIV compartment). After antigenic peptide is programmed cell death ligand 1 (PD-L1) on DCs interacts with
bound to MHC class II molecules, it exits the lysosomes through the programmed cell death protein 1 (PD-1) on T cells to downregulate
formation of long tubular structures, which simultaneously deliver T-cell responses. Inducible costimulator ligand (ICOSL) is present on
costimulatory molecules such as CD86 to the cell surface. 76,77 both DCs and B cells and is critical for germinal center formation
DCs handle internalized antigens in a specialized way unlike and immunoglobulin class switching.
other phagocytic cells such as macrophages, which degrade most of Signal 3 determines the skewing of the T-cell response such that
the internalized material, leaving only limited amounts of antigenic T cells may terminally differentiate either toward IFN-γ–producing
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peptides for presentation onto MHC molecules. On the contrary, CD4 T cells (Th1 cells), which eradicate intracellular pathogens
internalized antigens in cDCs are preserved for longer times, thereby (bacteria or viruses), or into Th2 cells producing IL-4, IL-5, and
allowing their transport by maturing DCs to secondary lymphoid IL-13, which promote elimination of extracellular infections.