This proposal represents a series of studies designed to assess a potential role for endogenous galectin-1 in regulating T cell development, activation, and tolerance induction. The rationale for the proposed experiments stems from our studies defining galectin-1 as novel T cell regulator, capable of tuning TCR signals to selectively modulate functional outcome. Through a unique molecular mechanism involving reorganization of T cell glycoproteins within the T cell synapse, we propose that galectin-1 opposes costimulator-induced lipid raft recruitment to the synapse and processive and sustained TCR signal transduction. Our preliminary findings predict that endogenous galectin-1 might function in setting TCR signaling thresholds during T cell development and in preventing T cell hyperactivity and autoimmunity. Galectin-1 is expressed abundantly throughout the thymus and can cooperate with TCR engagement to induce thymocyte apoptosis. Therefore, we propose to analyze the role of galectin-1 in TCR mediated thymocyte positive and negative selection (Aim 1). Galectin-1 is also expressed by a subset of activated T cells. In some mature T cell populations, galectin-1 can cooperate with TCR engagement to enhance apoptosis, while antagonizing IL-2 production. Furthermore, galectin-1 can skew a Th1 response to a Th2 response. Therefore, we propose to examine the role of galectin- 1 in mature T cell activation, differentiation and apoptosis (Aim 2). Finally, galectin- 1 expression is relatively high in resting CD4+CD25+ regulatory T cells (Treg) and its expression is increased to even higher levels in activated Treg cells. Like the putative Treg cell effector, galectin-1 can function in trans to antagonize IL-2 production by antigen responsive T cells. Therefore, we propose to examine the role of galectin-1 in Treg cell activity and the induction and the regulation of inflammatory bowel disease and tissue specific autoimmunity (Aim 3). While previous studies have primarily assessed the activity of T cell exposure to recombinant galectin-1, here we assess its endogenous activity. To address these issues we will analyze T cell development and responses of wild type and TCR transgenic T cells in which the galectin-1 gene has been ablated. In alternate approaches, we will characterize galectin-1 activity by differentiating or activating T cells in the presence of the newly developed galectin-1 inhibitor, L2hmda, or recombinant galectin-1. These studies will contribute to our basic understanding of T cell regulation, functional fate determination, and autoimmune disease prevention. Furthermore, they may identify novel targets for therapeutics aimed at inducing self tolerance for blocking autoimmunity and graft rejection or reversing tolerance to tumor antigens.
| Tomassian, Tamar; Humphries, Lisa A; Liu, Scot D et al. (2011) Caveolin-1 orchestrates TCR synaptic polarity, signal specificity, and function in CD8 T cells. J Immunol 187:2993-3002 |
| Motran, Claudia C; Molinder, Karen M; Liu, Scot D et al. (2008) Galectin-1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function. Eur J Immunol 38:3015-27 |
