Both mucosal immunity and tolerance are crucial for maintaining the integrity of the self. On the one hand, the mucosae are the major ports of entry for pathogens that ought to be expelled; on the other hand, the gut contains enormous amounts of dietary antigens that must be tolerated. The investigator's long-term goal is to elucidate the mechanisms of mucosal immunity and tolerance. This application is based on the investigator's recent observation that the costimulatory molecule B7 is constitutively expressed in mucosal lymphoid tissues, and that blocking B7 costimulation prevents the induction of mucosal tolerance. The working hypothesis is that the levels of B7 expression at the mucosa may dictate whether immunity or tolerance develops following mucosal administration of antigens and that B7:CTLA4 interaction may play pivotal roles in the development of mucosal tolerance.
Two specific aims will be investigated. 1) What are the roles of B7 in mucosal immunity and tolerance? The levels of B7 expressed at the mucosa can be reduced by specific blockage, or increased by adenoviral vector-mediated B7 gene transfer. In this aim, the investigator will examine whether different levels of B7 affect the fates of specific T-cells at the mucosa. The question of whether """"""""follicular T-cell exclusion"""""""" occurs in the Peyer's patch during mucosal tolerance will also be examined, and, if so, whether it can be abrogated by transient upregulation of B7. The fates of antigen-specific T-cells will be tracked in vivo using a T-cell receptor transgenic model. 2) What are the roles of CTLA4 in mucosal immunity and tolerance? The investigator has recently found that CTLA4 blockade at the time of mucosal antigen administration prevented the induction of T-cell tolerance. In this aim, the investigator proposes to examine the kinetics of CTLA4 expression during mucosal tolerance using the adoptive TcR transgenic model. The investigator will then generate CTLA4 deficient TcR transgenic mice by crossing CTLA4 deficient mice with TcR transgenic mice. The CTLA4 deficient ovalbumin-specific T-cells will then be adoptively transferred into normal mice and their reactivity to mucosal antigens examined.
