Targeting dendritic cells for priming cellular immune responses (original) (raw)
Dendritic Cells in Immune Response Induction
Stem Cells, 1996
The study of dendritic cells (DCs) has seen a rapid expansion in recent years, and their importance within the immune system is now widely recognized. Along with B lymphocytes and mononuclear phagocytes, DCs make up what are known as the professional antigen-presenting cells (APCs). These are cells which are capable of highly efficiently presenting antigens to the immune system in the context of both major histocompatibility complex class I and class II molecules. What makes DCs stand out from other professional APCs, however, is their seemingly unique ability to present antigen to T lymphocytes which have had no previous contact with antigen. This gives DCs a central role in the initiation of immune responses, and creates possibilities for their exploitation in the development of therapeutic strategies against tumors and other diseases.
Taking dendritic cells into medicine
Nature, 2007
Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumors can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but again DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy. Immunology is a major force in medicine. It is needed to understand how prevalent diseases (Fig. 1) come about and how to develop preventions and treatments. This broad reach of the immune system reflects its two functions: to recognize diverse substances termed antigens, and to generate many qualitatively distinct responses. Dendritic cells (DCs), named for their probing, tree-like or dendritic shapes (Gr. dendron, tree) 1,2 (Fig. 1), are pivotal for both: recognition of a universe of antigens and control of an array of responses. Previously, we reviewed some biological features of DCs 3,4. Here we illustrate medical implications of DCs, which control a spectrum of innate and adaptive responses. Innate immunity encompasses many rapid reactions to infection and other challenges 5-9. Adaptive immunity, in contrast, is learned or acquired more slowly, in days to weeks; it has two hallmarks: exquisite specificity for antigens, and a durable memory to develop improved function upon reexposure to antigen. Adaptive responses are either immunogenic, providing resistance in infection and cancer, or tolerogenic, leading to silencing as is desirable in transplantation, autoimmunity and allergy. To date, the successes of immunology in the clinic have largely been based on antibodies made by B cells, but T cell-mediated immunity, which has enormous yet untapped therapeutic potential will be stressed here. DCs are specialized to capture and process antigens in vivo 10-14 , converting proteins to peptides that are presented on MHC molecules and recognized by T cells. DCs also migrate to T cell areas of lymphoid organs where the two cell types interact to bring about clonal selection 15-17. The DC system is thus designed to harness the recognition repertoire of T cells, consisting of billions of different lymphocytes, each with a distinct but randomly arranged antigen receptor 18. This repertoire in turn represents a virtually infinite "drug library" for specific therapies that increase or decrease T cell function. Following clonal selection, DCs control many T cell responses. Antigen-selected T cells undergo extensive expansion, a thousand fold or more as a result of division at a rate as high as 2-3 cell cycles a day 19,20. Clones of lymphocytes are also subject to silencing or tolerance by socalled "tolerogenic DCs" 21-23 , which either eliminate (delete) 19,20,23-26 or block (suppress) T cells 27-39. If deletion is avoided, the clone undergoes differentiation to bring about an array of potential helper, killer, and suppressive activities. For example, under the control of DCs, helper T cells acquire the capacity to produce powerful cytokines like interferon-γ to activate macrophages to resist infection with facultative and obligate intracellular microbes (Th1 cells) 40-44 , or IL-4, 5 and 13 to mobilize white cells that resist helminths (Th2 cells) 45,46 , or IL-17 to mobilize phagocytes at body surfaces to resist extracellular bacilli (Th17 cells) 47-51. Alternatively, DCs can guide T cells to become suppressive by making IL-10 (Tr1 cells) 28,30,52,53 or by differentiating into foxp3 + cells 36,37,39. Finally, DCs induce the T cell clone to acquire memory, allowing it to persist for prolonged periods and to respond rapidly to a repeated exposure to antigen 54-58. Box 1, Location of DCs. DCs are a uniquely positioned, prime target for disease relevant stimuli. DCs are abundant at body surfaces like skin, pharynx, upper esophagus, vagina, ectocervix, and anus 419 , and at so called internal or mucosal surfaces, such as the respiratory and gastro-intestinal systems 61,62,364,420-423. DCs actually extend their processes through the tight junctions of epithelia, which likely involves DC expression of the tight junction proteins claudens and occludens, without altering epithelial barrier function 424. This increases DC capture of antigens from the environment 61,163 even when there is no overt infection or inflammation, probably allowing for the silencing of the immune system to harmless environmental antigens 26,363. DCs at body surfaces can function locally, e.g., to convert vitamins A and D to active retinoic acid and 1,25(OH) 2 D 3. One consequence of the overlooked metabolic capacities of DCs is to increase the homing of immune cells to that mucosal surface 425-427 and, in the case of retinoic acid, to help DCs differentiate suppressor T cells that block autoimmune and inflammatory conditions 428-431. After leaving peripheral tissues, DCs migrate with environmental, self, and microbial antigens to lymphoid organs, a process that is guided by chemokines 15,17 and can be enhanced by vaccination 432,433. DCs have now been studied in intact lymphoid tissues without the need for cell isolation. These are the sites where immune resistance and tolerance are initiated. The DCs create a labyrinthine system within T cell areas, while probing the environment through the continuous formation and retraction of processes 63 and displaying antigens and other stimuli needed to initiate responses by appropriate clones of specific T cells 434-438. New research reveals interactions of DCs in lymphoid tissues with other major classes of lymphocytes, B cells 423,439-448 and NK cells 257,260,261,449. Microbes also can alter the function of DCs so that they switch T cell responses from protective Th1 to nonprotective Th2, as in infections with Aspergillus fumigatus 140,141 malaria 142 , and hepatitis C 143 , or to IL-10 production in the case of Bordetella pertussis 144. At this time, there are no therapies that try to interrupt the microbial immune evasion pathways that are summarized above. Several microbes additionally can exploit DCs for purposes of replication and spread in the infected host. The lectin DC-SIGN/CD209 is used by dengue virus 145,146 and Ebola virus 147 to infect DCs. In the case of HIV-1, CMV, and Ebola virus, the lectin additionally sequesters virus within DCs, which later transmit infectious virus to other targets like T cells 147-153. DCs are
Extracellular antigen processing and presentation by immature dendritic cells
Proceedings of the National Academy of Sciences, 1999
In antigen presentation to CD4 ؉ T cells, proteins are degraded to peptide fragments and loaded onto class II MHC molecules in a process involving the peptide exchange factors H-2M (murine) or HLA-DM (human). In many antigen-presenting cells these processes occur in intracellular endosomal compartments, where peptides are generated and loaded onto class II MHC proteins for subsequent transport to the surface and presentation to T cells. Here, we provide evidence for an additional antigen-processing pathway in immature dendritic cells (DC). Immature DC express at the cell surface empty or peptide-receptive class II MHC molecules, as well as H-2M or HLA-DM. Secreted DC proteases act extracellularly to process intact proteins into antigenic peptides. Peptides produced by such activity are efficiently loaded onto cell surface class II MHC molecules. Together these elements comprise an unusual extracellular presentation pathway in which antigen processing and peptide loading can occur entirely outside of the cell.
Immunobiology of Dendritic Cells
Annual Review of Immunology, 2000
to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell-mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.
Journal of Experimental Medicine, 2000
The well defined, immature murine dendritic cell (DC) line D1 was used to study the role of DC maturation in CTL induction in vitro and in vivo. Maturation of D1 cells, characterized by markedly increased expression of MHC and costimulatory molecules, was induced by incubation with lipopolysaccharide, agonistic CD40 antibody, or specific CD4 ϩ T helper (Th) cells. Activated, but not immature, D1 cells efficiently primed alloreactive T cell responses in vitro. Similarly, priming of CTL immunity in vivo in CD4-depleted mice was only observed if these mice were immunized with activated D1 cells. This study provides formal evidence that activation of DCs, induced by Th-independent as well as Th-dependent stimuli, is essential for efficient induction of CTL responses.
Reviews on the Role of Dendritic Cells in Induction and Regulation of Immunity
2015
s: Dendritic cells (DCs) are the most potent professional antigen presenting cells and they arise from both the myeloid and lymphoid lineages. The review is made to overview the role of dendritic cells in controlling immunity. Dendritic cells in the periphery capture and process antigens, express lymphocyte co-stimulatory molecules, migrate to lymphoid organs and secrete cytokines to initiate immune responses. They not only activate lymphocytes, they also tolerate T cells to antigens that are innate to the body (self-antigens), thereby minimizing autoimmune reactions. Tissue dendritic cells phenotypes that do have a function in primary defense will be activated to mature after encountering and ingesting of antigens. Up on activation they express major histocompatebility complex and co-stimulatory molecules, secrete different cytokines and migrate to the secondary lymphoid organ for initiation of adaptive immune response. The dendritic cells play a central role in control and regulat...