. Dendritic cells (DC) are nature's adjuvant, potent inducers of helper and killer T lymphocyte responses. Distributed as sentinels throughout the body, DC are poised to capture antigens, migrate to draining lymphoid organs and, after a process of maturation, select antigen specific lymphocytes to which they present the processed antigens thereby initiating immune responses. Besides activating T lymphocytes, DC also tolerize T cells to self- antigens and are involved in the initiation of B cell immunity. There is an enormous complexity within the category termed """"""""dendritic cell."""""""" First, DC may be found in three distinct stages of differentiation/ maturation: patrolling precursor (DCpre), tissue residing immature DC (DCimm) and mature DC (DCmat) within the T cell rich areas and the germinal centers of secondary lymphoid organs. Second, recent studies suggest the existence of multiple DC subsets with possibly distinct functions. The scarcity of DC impeded the detailed studies of their function until methods for DC generation became available. For example, DCimm obtained by culturing monocytes with GM-CSF+IL-4 are the basis for virtually all-human clinical trials. However, the investigator and others have developed a system yielding large numbers of DC by culturing CD34+ hematopoietic progenitors with GM-CSF+TNF. They identified within these cultures two distinct DCpre, CDla+CD14-, and CDla-CD14+ cells which yield Langerhans cells and interstitial DC, respectively. They found striking functional differences between these DC subsets. In particular, 1a-CD14+DCpre differentitate initially into DCimm with high capacity for antigen capture, and subsequently into DCmat with the unique capacity of inducing naive B cells to differentiate into IgM secreting cells, in response to CD40 triggering and IL-2 (B cell priming). To further knowledge of DC biology, it is necessary to define the function of distinct DC subsets, to determine their interactions with lymphocytes, and to define the relationship between in vitro and in vivo DC subsets.
The specific aims of this proposal can be summarized as follows: 1) Establish the relationship between in vitro and in vivo DC, 2) Explore the molecular mechanisms explaining the differential effects of specific DC subsets on B cell functions, 3) Determine whether specific DC subsets skew T cells towards a Th1 or Th2 phenotype, 4) Determine whether specific DC subsets differentially capture and process apoptotic bodies. Addressing these questions will provide a better understanding of the DC system in the initiation of immune responses. These studies should also permit more effective use of DC for the immunotherapy of cancer and infectious diseases.
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