Dendritic Cells: Biological and Pathological Aspects (2008)

Our skin and mucosa are covered by considerable numbers of microbes, yet we stay healthy. However, when the microbes break these barriers, the immune system faces several challenges. First, it needs to decide whether or not to respond. Second, if a response is made, it must be tailored to fight that particular microbe. Generating the right class of immune response can be a matter of life and death itself. For example, in leprosy, the tuberculoid form of the disease is characterized by a Type 1 response which keeps the disease in check, but the lepromatous form induces an often fatal Type 2 response (1 , 2) . Microbe-specific immunity must therefore limit the extension of the infection as well as remove the infected cells. This requires the participation of different cells of the innate immune system as well as cells of the adaptive immune system, specifically T and B lymphocytes that are educated and activated by dendritic cells (DCs; ref. (3) . Studies to characterize DCs started in the 1970s (4) , but the techniques to generate DCs in vitro were discovered in the 1990s (5 – 8) , allowing the identification of many of their biological and molecular properties. The current vaccines, essentially designed by microbiologists, rely on the generation of antibody responses. However, the development of T cell-mediated immune responses is required for chronic diseases for which no effective vaccines exist. The initiation of T-cell immunity poses several challenges. First, the frequency of microbe-specific T cells is extremely low. Second, infected cells express very few peptide-MHC complexes recognized by the specific T cells (100 or less per cell). Third, infected cells lack the co-stimulatory molecules needed to drive T cell clonal expansion and the production of cytokines, thus lacking the capacity to generate cytotoxic/helper T cells. These challenges are overcome by DCs, which capture microbes, present their antigens, and provide signals necessary for T-cell expansion and differentiation. There are two different paths for the uptake of microbial antigens by DCs: 1) the “classical” way where DCs in tissues capture the invading microbes and migrate into secondary lymphoid organs, and 2) the “novel” way where the microbial proteins are rapidly drained into secondary lymphoid organs and captured by lymphoid-resident DCs ( Figure 44.1 ). Both migrating DCs and DCs resident in lymphoid organs undergo maturation and activate antigen-specific T cells. DCs are also important in launching humoral immunity partly through their capacity to directly activate B cells (9 , 10) . They also activate innate immune cells, such as natural killer (NK) cells (11 , 12) and natural killer T (NKT) cells (13) . In addition to the ability to recognize and eliminate what is foreign or aberrant, the immune system has built-in tolerance mechanisms to ignore components of “self” (14) . DCs appear to be essential in the maintenance of immunological tolerance both in the thymus and in the periphery (14) . Thus, their alteration might contribute to the break of tolerance and thereby to the pathogenesis of autoimmune diseases. Just like lymphocytes, DCs are composed of several subsets with distinct functions (15) . This review will emphasize the role of DC subsets in disease pathogenesis and how we can exploit these subsets for therapy.