Immunotherapy for Infectious Diseases

Dendritic Cells 103
tion that infection with influenza virus results in activation of DCs to such an extent
that the cells are capable of activating CD8� T-cells directly, bypassing the usual
requirement for CD4� T-cell help (61).
CTLs are thought to contribute to hepatitis B virus (HBV) clearance by killing
infected hepatocytes and by secreting antiviral cytokines (62). HBV transgenic mice
that are immunologically tolerant to HBV-encoded antigens represent a model of
chronic HBV infection suitable for use in the development of therapeutic immunization
strategies. Using this model, investigators have recently shown that antigen presentation
by DCs can break tolerance and trigger an antiviral CTL response (63).
In general, bacterial products processed by DCs are presented in the context of MHC
class I and II molecules on the cell surface to T-cells. In addition to classical MHC
molecules, DC express CD1, a molecule related in structure to MHC molecules that is
involved in presenting non-protein antigens to T-cells. In this regard, the presence of
CD1� DCs at sites of Mycobacterium leprae infection has been associated with an
improved clinical outcome (64). Moreover, recent studies indicate that human DCs can
present Mycobacterium tuberculosis antigens to CD1-restricted T-cells in vitro (65).
Taken together, these results suggest that DCs play a critical role in the induction of
protective immunity against a variety of infectious organisms. On the other hand, several
organisms have evolved mechanisms to inhibit the ability of DCs and other APCs
to process and present antigens, thereby hindering the development of protective
immunity. Useful reviews of this topic have appeared (54,66).
ONTOGENY AND PHENOTYPIC
IDENTIFICATION OF DENDRITIC CELLS
The same attributes that make DCs potent APCs make them ideal vehicles to deliver
pathogen- or tumor-associated antigens for immunotherapy or prophylaxis. As noted
above, antigen-pulsed DCs have been shown to confer protection against infection in
numerous animal models. Alternatively, DCs might be used to deliver immunemodulating
and antimicrobial cytokines and chemokines such as IL-12, IFN-�,
RANTES, and fractalkine to sites of infection or inflammation in vivo (67–72). A
potential advantage of this approach is the ability to target the delivery of immunomodulatory
products to sites of DC/T-cell engagement where they will exert maximal
effects and minimal systemic toxicity. Before considering how this might be accomplished,
it is necessary to review our current knowledge of the life cycle of DCs,
including the changes in their phenotype that occur with maturation and activation and
the molecules that mediate their interactions with T-cells.
DC precursors are derived from CD34+ hematopoietic progenitor cells. These precursors
migrate from the bone marrow and circulate in the blood to specific sites in the
body, where they mature and act as sentinels for the immune system (73). This trafficking
to the tissues is directed by expression on DCs of the chemokine receptors
CCR1, CCR5, and CCR6 as well as adhesion molecules such as the CD62P-ligand
(74–76). Tissue-resident DCs, including Langerhans cells in the skin, hepatic DCs in
portal triads, mucosal DCs and lung DCs, take up, process, and present antigens to
T-cells in the context of MHC class I and II molecules. The DCs present in peripheral
tissues are efficient at taking up and processing antigen (microbial proteins or
apoptotic bodies [77,78]) but not at presenting them to T-cells. Antigen-independent