DCs as targets for vaccine design
Introduction
DCs are the most potent APCs used by the immune system, and are therefore a very attractive target for the designer Ags that can be used either as conventional vaccines or for DC-based therapies. As a result of the technical advances made in the last decade in isolating, purifying, and propagating DCs, we are now able to study their functions. Genechip technologies and sophisticated flow cytometric techniques have allowed multiple subsets of DCs to be identified by their specific surface markers, and have also opened the way for discovery of the molecular mechanisms that determine their functions. Different DC subsets and DCs at different stages of development or activation express distinct surface molecules and secrete cytokines that selectively determine the type of immune response which is induced. These properties suggest that DC subsets are amenable to specific targeting through these surface molecules and, consequently, allow greater efficacy for vaccine delivery. As the role of different DC subsets becomes known, it is likely that even more efficient vaccines will be developed to elicit particular types of immune response.
Section snippets
DC maturation and activation
The primary function of DCs is to capture Ag, process it and present antigenic peptides to activate specific T cells [1]. Found in most lymphoid and non-lymphoid organs of the body, DCs are widely distributed, acting as sentinels for tumor and infection detection [2]. DCs have long been considered to be the main APCs involved in priming both CD4 and CD8 T lymphocytes. DCs are perfectly equipped for their role as initiators of the immune response [3,4]. They express both Class I and Class II MHC
MHC Class I and II Ag presentation—the ‘Classical’ pathways
Typically, MHC Class I molecules present endogenous self-Ags or pathogen-derived Ags that are synthesized within a cell. Exogenous (extracellular) Ags are usually processed through the MHC Class II pathway, and are then presented to CD4+ T cells. Cytotoxic (CD8+) T cells (CTL) recognize peptides that are presented by MHC Class I molecules, while helper (CD4+) T cells recognize Ags presented on MHC Class II molecules. All nucleated cells possess MHC Class I molecules, but MHC Class II molecule
DC subtypes
DCs in mice and humans are a heterogeneous population of cells that can be segregated into several phenotypically defined populations. Much effort is currently directed at elucidating the functional relevance of each of these populations.
Human DC subtypes in vivo
The study of human DCs has been hampered by the lack of availability of human lymphoid tissues that allow direct comparison with murine DC subsets. In contrast to the many DC subtypes identified in the mouse, relatively few DC subsets of mature human DCs have been identified (Table 4).
In general, human DC populations express the markers CD11c, CD11b and CD4, but the human equivalent of the murine CD8α+ DC remains elusive. Langerhans cells, a subset of human DCs, are characterized by the
Host—pathogen interactions and in vivo identification of DC subsets for priming
By monitoring the environment, and detecting and reacting to Ags, DCs form a link between the innate and adaptive immune systems. A newly emerging theme in DC biology is that of understanding the specialized functional role that DC subsets play in triggering different components of the immune system.
The DCs responsible for CTL priming following Herpes simplex 1 (HSV-1) infection appears to be the CD8+(CDllb_) DC [45]. This is the same subset of DC that preferentially cross-present soluble and
Determining the outcome of Ag delivery and presentation using DC subsets
The last decade has seen the execution of a large number of technically precise experiments, particularly in murine models, that have uncovered a large array of DC subsets in vivo. Functional definition of the importance of these specialized DC subsets in an immune response has been much slower and is only now beginning to emerge. These advances have opened the door to specific customized targeting of Ags to DC populations, in attempts to generate effective Ag delivery systems that will improve
Targeting DCs to induce tolerance
In most situations, the objective of vaccination is to initiate or enhance an immune response, however, controlling an immune response (inducing anergy or tolerance) is equally complex. When a DC captures Ags from a pathogen, for example a virus, then both viral and self-Ags will be presented to the immune system in order to activate the cellular arm of the immune system to eliminate the virus. Thus, a mechanism is required to allow removal or control of the virus without attacking the body's
Developing smart vaccines
The variety of DC phenotypes, and the multiplicity of different lymphoid cells with which DCs can engage, indicate that once they have encountered Ag, DCs are intimately involved in determining the nature of the ensuing immune response. It is not surprising, therefore, that their importance in re-thinking vaccine design has already been described by others (for review see Reference 60).
DCs have been described as’ Nature's adjuvants’ and, indeed, once they can be persuaded to take an interest in
Obstacles facing the study of DCs
Although the idea of using DCs as vehicles for vaccine delivery and for cell-based therapy is not new (for review see Reference 60), their utility has been hampered by a number of obstacles:
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Although DCs are widely dispersed through the host, they are present only in small numbers
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Difficulties have been encountered in developing robust isolation procedures for DCs
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In vitro culture conditions cause phenotypic changes in DCs that are not representative of the corresponding in vivo isolates; related
Acknowledgements
We would like to acknowledge Meredith O’Keeffe for her critical reading of this manuscript. Gabrielle Belz is a Wellcome Trust Senior Overseas Research Fellow. David Jackson is a Principal Research Fellow with the National Health and Medical Research Council of Australia, and Program Leader of the Cooperative Research Centre for Vaccine Technology.
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