T cells are one of the key cells in the immune system. Although they are
not the first line of defense against a pathogen, their functions can greatly enhance
the phagocytosis and destruction of pathogens as well as the development of
antibody responses. Furthermore, even when responding T cells have facilitated
the clearance of the pathogen, they can avoid death to become long-lived cells that
"remember" encountering the pathogen for years afterward. This long-term
memory allows subsequent immune responses to improve with each exposure,
ultimately preventing disease upon reinfection. The activation of these T cells
depends on specific recognition of antigen along with a costimulatory signal. This
activation process is well studied, but not completely understood. Additionally, the
mechanism behind memory T cell development is still very much unknown. In the
work presented in this thesis, delivery of costimulatory signals via CD4O and 0X40
were studied using an in vivo superantigen (SAg) model of T cell stimulation. In
the context of this two-signal (SAg + costimulation) model, both CD4O and OX40
could deliver signals that enhanced SAg-reactive T cell clonal expansion, but they
could only partially prevent T cell death. Coadministration of the inflammatory
agent lipopolysaccharide (LPS), however, could keep increased responder T cell
populations alive for at least two months. Interestingly, this three-signal (SAg +
costimulation + LPS) induced survival was not dependent on proinflammatory
cytokines or activation of the transcription factor NF-KB, but was sensitive to the
immunosuppressant cyclosporin A (CsA). The mode of action of CsA may point to
the mechanism driving long-term T cell survival. Additionally, examination of
early time points after three-signal stimulation suggested more clues to the
mechanism of survival induction. The cytokines IL-2 and TNF-�� seem to be
involved early on, but for now, little is known about their complete role. Thus, the
goal of this work was to investigate the costimulatory and adjuvant-mediated
signals required for memory T cell development. Ultimately, an understanding of
how memory T cells can be generated could be used to enhance vaccine efficacy or
shut off autoimmune conditions. / Graduation date: 2002
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/32495 |
| Date | 14 September 2001 |
| Creators | Maxwell, Joseph R. |
| Contributors | Vella, Anthony T. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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