| dc.description | Antibody-mediated Thy-1 stimulation was first shown to activate T cells more than two decades ago. Since then, our knowledge of the mechanism of Thy-1 signal transduction has remained limited, in large part due to the absence of a known stimulatory Thy-1 ligand in the lymphoid compartment. We therefore also know little of the function of this glycophosphatidylinositol-anchored protein, beyond T cell mitogenesis. The purpose of this work was to enhance our understanding of the nature, and role, of Thy-1 signaling in T cells. In the context of Thy-1- and CD28-mediated T cell activation induced by monoclonal antibody (mAb)-coated microbeads, I found that extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) each carry out different, but important, roles. The major function of ERK1/2 is to mediate interleukin (IL)-2 expression, while JNK is involved in the production of IL-2 and surface expression of the IL-2 receptor (IL-2R) alpha chain (CD25). Interestingly, in addition to mediating IL-2R signal transduction, p38 MAPK also negatively regulates IL-2 gene transcription. The observation that a Thy-1 signal per se induces CD25 expression in T cells allowed me to use a panel of selective pharmacological inhibitors to identify components of the Thy-1 signaling pathway. Thy-1-induced CD25 expression is dependent on ERK1/2, JNK, phospholipase C, protein kinase C, calmodulin-dependent kinase II, calcineurin, phosphatidylinositol-3 kinase, and protein kinase A, many of which are also associated with T cell receptor signaling. Unexpectedly, I found that p38 MAPK is not involved in Thy-1-induced CD25 expression. Lastly, I discovered that Thy-1 signaling induces an atypical regulatory phenotype in normal T cells. mAb-mediated stimulation of Thy-1 on CD4+CD25 - forkhead box protein P3 (FoxP3)- T cells generates CD4+CD25+FoxP3- T cells that do not proliferate in response to CD3/CD28 stimulation despite producing substantial amounts of IL-2, and are able to suppress normal T cell responses. Taken together, my findings clarify the role of MAPKs in Thy-1-induced T cell activation, reveal elements of the Thy-1 signal transduction pathway in T cells, and suggest a novel function for Thy-1 in the induction of atypical regulatory T cells. | en_US |
