Electronic Thesis/Dissertation


Regulation of T cell Receptor Signaling by the Protein Tyrosine Phosphatase, CD45 Open Access

CD45 is the primary protein tyrosine phosphatase present on all nucleated hematopoietic cells. Studies in CD45 deficient cells and animals have shown that CD45 is required for antigen receptor signaling and lymphocyte development, indicating an overall positive effect on T cell receptor (TCR) signaling. However, recent studies have shown that cells with modest reductions in the expression of CD45 result in augmentation of TCR signaling when stimulated with antibodies against CD3 and increased thymocyte development. These studies suggest that the regulation of CD45 activity is critical for tuning the sensitivity of T cell activation; however the mechanisms in which CD45 regulates TCR signaling are largely unknown. Here we expand on current data by stimulating T cells expressing a transgenic TCR with specific peptides of varied affinity, as well as visualize TCR via TIRF microscopy to more closely mimic active in vivo signaling. We show that while TCR signaling is relatively CD45-independent when stimulated with peptides of high affinity, T cells with reduced expression experience activation sooner and longer than wild type T cells. TIRFM of actively signaling T cells with reduced CD45 demonstrate an accelerated and persistent activation when compared to wild type cells, implicating CD45 in the down regulation of TCRs. In addition to increase in TCR activity, recently published data demonstrates that reduced CD45 expression provides a protective effect against the lethal effects of some infections. In contrast to this data, we show that reduced expression of CD45 renders mice more susceptible to Toxoplasma gondii.

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