REVIEWS
Dendritic cells (DCs) are a sparsely distributed,migra-tory group of bone-marrow-derived leukocytes that are specialized for the uptake,transport,processing and pre-sentation of antigens to T cells 1–3.At an ‘immature’stage of development,DCs act as sentinels in peripheral tis-sues,continuously sampling the antigenic environment (FIG.1).Any encounter with microbial products or tissue damage initiates the migration of the DCs to lymph nodes (LNs).The antigenic sample at the time of the DANGER ,including
any microbial products,is processed and fixed on the DC surface as peptides that are pre-sented by major histocompatibility complex (MHC)molecules.The DCs also upregulate the co-stimulatory molecules that are required for effective interaction with T cells.In the LNs,the now-mature DCs efficiently trigger an immune response by any T cells with a receptor that is specific for the foreign-peptide–MHC complexes on the DC surface.
Immunoregulation by DCs
DCs as determinants of tolerance.The model of DCs as natural ADJUV ANTS that promote the immune response to foreign antigens has been modified after the realization that the antigen-presenting cells (APCs) that are involved in immunity must also be involved in tolerance to self-antigens.Central tolerance of T cells in the thy-mus,which is achieved by inducing the apoptotic death of potentially self-reactive T cells,is mediated by thymic DCs 4.Are these DCs specially armed to induce T-cell
death rather than proliferation? The evidence so far indi-cates that it is the stage of T-cell differentiation,rather than the type of DC,that determines the negative out-come of this interaction 5.Nevertheless,thymic DCs do have a life history that differs from the standard model,because most
of them derive from an intrathymic pre-cursor and develop and die within the thymus 6.A non-migratory behaviour seems to be more appropriate to such DCs,the function of which is to present self-antigens rather than to collect foreign antigens.
However,not all self-reactivity is eliminated from the T-cell receptor repertoire by central tolerance 7.Because the DCs that carry foreign antigens into the LNs must also be carrying self-antigens 8,the DCs themselves are likely to be responsible for tolerance as well as immunity.Tolerance to self-antigens in vivo seems to require an active,proliferative response by the self-antigen-reactive T cells 9.Accordingly,the prolifera-tive responses of T cells to DCs in culture are as likely to model the initiation of tolerance as the initiation of a protective immune response.
Two general mechanisms have been proposed by which DCs might maintain peripheral tolerance.The first is that a subtype of specialized regulatory DCs is involved;there is some evidence for such DCs,but no consensus 10–12.The second is that all DCs have a capac-ity for initiating tolerance or immunity,the distinction depending on the maturation or activation state of the DC (FIG.1).The original concept was that IMMATURE DCS
MOUSE AND HUMAN DENDRITIC CELL SUBTYPES
Ken Shortman* and Yong-Jun Liu ‡
Dendritic cells (DCs) collect and process antigens for presentation to T cells, but there are many variations on this basic theme. DCs differ in the regulatory signals they transmit, directing T cells to different types of immune response or to tolerance. Although many DC subtypes arise from separate developmental pathways, their development and function are modulated by exogenous factors. Therefore, we must study the dynamics of the DC network in response to microbial invasion. Despite the difficulty of comparing the DC systems of humans and mice, recent work has revealed much common ground.
proliferation
*The Walter and Eliza Hall Institute of Medical Research,Victoria 3050,
Australia.‡
DNAX Research Institute,Palo Alto,
California 94304,USA.e-mails: shortman@wehi.edu.au,yong-jun.
DOI:10.1038/nri746
R E V I E W S
Figure 3 | CD8+dendritic cells (DCs) isolated from mouse spleen.The DCs were extracted and enriched from mouse spleen42and then sorted as CD11c+CD8α+cells. The sorted cells were incubated overnight in culture medium, which activates the DCs. Surface major histocompatibility complex class-II (MHC-II) molecules were then stained red (with anti-

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