Apoptosis is a fundamental regulatory process in development, morphogenesis and in control of the immune system. Despite the importance of this process in both basic developmental programs and in pathologic conditions, little is known about the molecules which can trigger apoptosis. Our laboratory has recently demonstrated that galactin-1, an endogenous carbohydrate binding protein, can induce apoptosis of human thymocytes and activated T-cells. Galactin-1 is a member of a family of animal lectins, homologues of which are expressed in species from sponges and C. elegans to humans. In human lymphoid tissue, galactin-1 is expressed by stromal cells in thymus, lymph nodes (LN) and spleen. Galactin-1 binds four T-cell surface glycoproteins, including CD45 and CD43, and CD45, a tyrosine phosphatase, is required for galactin-1 induced apoptosis. This application examines the mechanism of galactin-1 induced T-cell apoptosis, focusing on the structural features of the T-cell surface counterreceptors required for galactin-1 binding and signaling, and on the initial steps in the galactin-1 signaling pathway.
The specific aims of the application are: 1. To characterize features of the oligosaccharide and protein components of T-cell surface counterreceptors which are important for transducing the galactin-1 signal to die. 2. To examine the pattern of counterreceptor cross-linking subsequent to galactin-1 binding, and whether specific cytoplasmic molecules associate with counterreceptors in galactin-1 treated cells. 3. To characterize regions of the CD45 phosphatase domain essential for galactin-1 induced apoptosis, and to examine the effects of galactin-1 binding on cellular tyrosine kinases. The experiments in this application will contribute to our understanding of the different pathways which can lead to the final endpoint of apoptosis, and will also suggest novel approaches to modulating T-cell proliferation in pathologic processes such as autoimmune disease and lymphoid malignancies.
