This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Asbestos exposure is linked with the induction of a variety debilitating and potentially fatal human diseases such as pulmonary fibrosis and mesothelioma. The mechanisms by which asbestos induces fibrosis and/or neoplastic transformation are unclear. Cytokines including TGF and TNF are critical mediators of asbestosis and mice lacking both TNFRI and TNFRII are not susceptible to asbestos induced pulmonary fibrosis. These findings suggest a role for the immune system in modulating asbestos-related diseases. A recent study from Pfau et al. identified immunological abnormalities in the residents of Libby, MT. Libby was contaminated with amphibole asbestos as a result of vermiculite mining and processing that took place between the early 1920's and 1990. Libby residents have increased serum Ig and elevated levels of auto-antibodies. Taken together, these findings strongly suggest that exposure to amphibole asbestos modulates immune function. To address the effects of amphibole asbestos on immune function this proposal focuses on the activation and differentiation of CD4+ T helper cells, a key event in the generation of an immune response. CD4+ T cells provide cytokine and contact-dependent help to B cells boosting immunoglobulin secretion and allowing for isotype switching. The interaction of a specific T cell antigen receptor (TCR) with the cognate MHC:peptide ligand on an APC rapidly initiates intracellular signaling. We and others have shown that this initial signaling leads to the large-scale redistribution of cytoplasmic and membrane-bound proteins to the site of T-APC interaction. These molecules are segregated both spatially and temporally into distinct regions within the interface called supramolecular activation complexes. The accumulation and segregation of these molecules leads to formation of the immunological synapse (IS). The IS is the location of sustained intracellular signaling necessary for full activation and differentiation to effector T cells. It is also the site of cytolytic granule release by CD8+ T cells and the location of secretion for a subset of effector cytokines by CD4+ T cells. The molecular constituents of the immunological synapse can have a significant impact on the activation state of the T cells. To date, no studies have undertaken a systematic approach to examine effects of amphibole asbestos on IS formation or T lymphocyte activation at the molecular level. In this proposal we will examine the formation and characterize the composition of the immunological synapse.
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