| dc.description.abstract | T lymphocytes are cells that play an essential role in both the regulation and activation of an immune response. The T cells role is two-fold: they migrate to an inflammatory site by interacting with endothelial cells lining the blood vessels and upon reaching the site of inflammation, interact with antigen presenting cells to facilitate clearance of the invading microorganism. The cell surface molecules ICAM-1 and LFA-1 play a large role in the function of T lymphocytes. These proteins act as counter-receptors that mediate both migration and activation. Proper regulation of T cell activation requires two costimulatory signals, one from the T cell receptor (TCR)-CD3 complex and the second from a surface molecule on an antigen presenting cell (APC). The first signal is characterized by the TCR-CD3 complex binding cognate antigen as it is being presented on a major histocompatibility complex (MHC) molecule. The second signal involves binding of a costimulatory molecule on the surface of a T cell, usually CD28, with a counter receptor present on the surface of an APC. ICAM-1, the focus of the present work, is located on the surface of T cells and functions in adhesion and extravasation of the cell during inflammation. Our lab and others have previously published that ICAM-1 can also act as a costimulatory molecule capable of delivering the second signal for T cell activation independent of the more traditional second signal, CD28. In the present work, we elucidated the components of the signaling complex formed after stimulation through ICAM-1. The proteins identified thus far include mitogen- activated protein kinase (MAPK), CD45, LFA-1, LAT, Gads, the Src tyrosine kinase family proteins Lck and Fyn, and the ZAP-70/CD3ζ complex. Since the ICAM-1/LFA-1 interaction is essential for proper T cell function, blocking the interaction could be a useful means of regulating improper immune response thus treating the diseases associated with its dysfunction. Previous studies in our lab using peptides derived from ICAM-1 and LFA-1 have proven beneficial in treating several autoimmune diseases. Here we sought to test a shorter course of peptide therapy and evaluated the treatment in a model for type I diabetes. The peptides not only delayed the onset of diabetes in the treated animals, but also drastically reduced the amount of infiltration seen within the islets of the pancreas. In addition to the diabetes study using the native peptides, we also used computational approaches to develop an alternative set of peptides with an increased affinity for ICAM-1 and LFA-1 and assessed their effect on T cell activation and function. We found that both peptides were able to inhibit MDHC-induced T cell adhesion in a clumping assay indicating specificity for both ICAM-1 and LFA-1. We also found that stimulating with anti-CD3 in the presence of each peptide caused a marked increase in proliferation of human T cells. This result suggests that the redesigned peptides are capable of acting as a costimulatory signal themselves. | |
