Immunotherapy for Infectious Diseases

104 Kundu-Raychaudhuri and Engleman
“danger” signals such as lipopolysaccharide (LPS), interferon (IFN)-� and -�, IL-1�,
and immunostimulatory DNA sequences present in many bacteria are required for DC
activation, which is accompanied by dramatically increased expression of MHC class
I and II molecules, costimulatory molecules, and other molecules (for example, adhesion
molecules) that contribute to DC-mediated T-cell activation (79). Once activated,
DCs leave the tissues and migrate via the afferent lymphatics to the T-cell-rich paracortex
of the draining lymph nodes, drawn by the chemokines MIP-3� and secondary
lymphoid-tissue chemokine (SLC) through upregulation of their chemokine receptor
CCR7 (80,81). Activated DCs secrete chemokines, e.g., RANTES, that attract naïve
and memory T-cells for priming (82). They also secrete IL-7 and IL-12, which induce
T-cell proliferation and B-cell differentiation (83,84) and Th1 immune responses,
respectively. This stimulatory milieu produced by activated DCs, combined with the
presentation of epitopes of antigens associated with MHC class I and class II determinants
and the expression of costimulatory and adhesion molecules, results in the generation
of potent antigen-specific CD4� and CD8� T-cell responses (85).
In humans there remain difficulties in identifying cells of the DC lineage because
no specific marker for these cells has been identified. Human myeloid precursors in
peripheral blood express CD2, -4, -13, -16, -32 and -33. With DC maturation, these
antigens are gradually lost from the cell surface (86). By contrast, MHC antigens,
costimulatory molecules, and adhesins increase with maturation. CD83 is expressed
on most activated or mature DCs (87), and antibodies to this molecule label such
cells preferentially (88). However, CD83 and other markers of mature DCs are absent
or only weakly expressed on DC precursors. Therefore, the identification and isolation
of such precursors still requires the exclusion of cells bearing lineage markers such
as CD3 (T-cell), CD14 (monocyte), CD19, -20, and -24 (B-cell), CD56 (NK cell),
and CD15 (granulocyte), as well as inclusion criteria, typically MHC class II expression
(89).
Committed DC precursors as well as activated DCs also typically express adhesins
and costimulatory molecules that although not specific for DCs can aid identification
(90,91), including CD11a (leukocyte function-associated antigen [LFA-1]), CD11c,
CD50 (intercellular adhesion molecule [ICAM-2]), CD54 (ICAM-1), CD58 (LFA-3),
and CD102 (ICAM-3). DCs possess nonspecific antigen uptake receptors although at
lower levels than macrophages. Some DC express Fc�R (CD16, CD32) and complement
receptors (CD11b, 11c, CD35). CD11c may also act as a receptor for LPS, as
DCs lack the classical LPS receptor, CD14, and yet respond to this stimulus. DCs also
can take up antigen through mannose receptors, potentially through the receptor recognized
by the DEC-205 antibody (92).
With activation and migration of DCs from peripheral tissues, antigen uptake activity
and the associated antigen receptors of DCs are downregulated. As a result, the
main function of these cells switches from antigen uptake to antigen presentation (93).
DCs are capable of processing antigen via classical pathways, e.g., breakdown of
endogenous antigens in the proteosome followed by transfer of peptide fragments into
the MHC class I compartment, and transport of exogenous antigens via endocytic lysosomes
into the MHC class II compartment (94). DCs also possess alternative pathways
of antigen processing and can route soluble antigen into the MHC class I pathway
through a mechanism known as crosspriming (95). DCs may also utilize molecular