Recently it has become apparent that innate immunity can regulate aspects of the adaptive immune response.
The aim of this proposal is to determine how dendritic cells (DC), cells of innate immunity, regulate cytotoxic CD8+ T cell responses to pathogens. To date much has been elucidated in terms of the role DC play during the initiation phase of adaptive immune responses. In particular these very potent antigen-presenting cells are critical for the initiation of antiviral CD8+ T cells responses. Mature DC expressing appropriate co-stimulation molecules are required to present antigen in order to initiate the activation of naive CD8+ T cells. What is not known, however, is whether DC play a role in the later expansion and contraction phases of the CD8+ T cell response. We have preliminary data showing that a great influx of DC occurs in the lungs of influenza type A virus infected animals 2-5 days postinfection and that costimulation is required during the later phases of the virus-specific CD8+ T cell response. By using DTR-CD11c transgenic animals we plan to deplete DC during different phases of the CD8+ T cell response and thus start to understand what role DC are playing during the later phases of CD8+ T cell response. The requirement of costimulation molecules such as CD28 or CD27 will also be investigated to delineate the mechanism of action of DC at these later stages of the response. Finally, the role of DC and whether costimulation is required in secondary CD8+ T cell responses is largely unknown. To date the classical costimulation pathway through CD28 has been extensively studied during the initiation phase of the immune response and found to be required for the maximal anti-viral CD8+ T cell response to take place. Its involvement in secondary responses is however not known even though some memory CD8+ T cells are known to express CD28. We will investigate the role of DC and the contribution of CD28 and CD27 in the secondary response and the generation of memory. In order to understand what the role of these DC is, we will investigate what are the characteristics of these pulmonary DC, whether they are infected, whether they present antigen and what cytokines they make. Finally, the mechanism that controls the migration of DC into the lungs will be investigated. The studies proposed here are novel as no previous study has examined how DC regulate expansion, contraction and the generation of memory during the later phases of the cytotoxic CD8+ T cell response. Elucidating the DC and costimulation requirements of cytotoxic CD8+ T cell responses may ultimately lead to the development of novel therapeutic and vaccine strategies against tumors and viral infections.
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