| dc.description | Although the glycosylphosphatidylinositol-anchored protein Thy-1 has been implicated in the process of T cell activation, the exact function of Thy-1 in this context has not been established. A number of roles have been proposed for Thy-1, ranging from negative regulation to costimulation of T cell responses. Moreover, the relationship between Thy-1 and the T cell receptor (TCR) has remained highly controversial. This work was undertaken to address several unresolved issues regarding the role of Thy-1 signaling in the induction of T cell proliferative and cytotoxic responses in the presence or absence of TCR signaling and/or appropriate costimulation. I found that antibody-mediated blockade of Thy-1 prevented the induction of non-specific cytotoxic T lymphocytes (CTLs) in response to anti-CD3 monoclonal antibody. This indicates that Thy-1 plays an important role not only for the effector phase of T cell-mediated cytotoxicity as has previously been described for CTL clones, but also during the induction phase of a CTL response. Taking advantage of selective pharmacological inhibitors of intracellular signaling molecules, I demonstrated that the TCR- and Thy-1-associated signal transduction pathways are not identical, with the p38 mitogen-activated protein kinase being a noticeable point of difference. Finally, I discovered that antibody-mediated triggering of Thy-1 in the context of strong, CD28-mediated costimulation provided by dendritic cells, leads to robust T cell proliferation, interleukin-2 synthesis and the acquisition of cytotoxic effector molecules, but not cytotoxic effector function. This finding has led me to propose that Thy-1 triggering may provide a non-classical form of signal 1 for select features of T cell activation. Collectively, my results point to the existence of fundamental differences between the TCR- and Thy-1-driven signaling pathways in T lymphocytes, and also suggest a novel role for Thy-1 as a potential source of signal 1 for T cell activation. | en_US |
