The objective of this research is to understand the cellular and molecular events which lead to antigen-specific transplantation tolerance in a defined model system of receptor ligation which induces TH2, anergy, and tolerance. CD2 is a major adhesion receptor, important for transducing signals for the T cell activation at the time of antigen presentation and priming. Concurrent engagement of CD2 at the time of TCR binding of antigen-MHC complexes results in a series of integrated signals which enhance T cell activation. Conversely, the investigators have shown that ligation of CD2 prior to TCR engagement shifts signaling pathways such that T cell activation is inhibited and antigen-specific transplantation tolerance is induced. CD2 ligation prior to CD3 ligation also results in T cell anergy in vivo and in vitro, induction of TH2-mediated suppression, and dissociation of CD3 signaling subunits. The hypothesis of the research is that D2 interacts directly or indirectly with the TCR/CD3 complex and that ligation of CD2 results in changes in TCR/CD3 structure and function which result in tolerance, anergy, or suppression.
The first aim will define the cellular events induced by CD2 during the induction and maintenance of antigen-specific tolerance in a murine cardiac allograft model. Experiments will examine grafts and graft infiltrating cells for expression of cell surface receptors and cytokines and determine the roles of these structures in induction and maintenance of tolerance. Particular emphasis will be placed on analyzing the role of putative TH2 suppressor cells and cytokines. An in vivo model for human CD2 will be developed using transgenic mouse strains.
The second aim will define the molecular events associated with CD2 related signaling. Particular emphasis will be placed on analyzing the effect of D2 ligation on TCR/CD3 expression and function. Novel molecules interacting with the conserved CED2 cytoplasmic domain will be isolated using the yeast two-hybrid system.
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