Virus-specific memory CD8+ T cells play a prominent role in protection of a host from recurring and persistent virus infection. It is known that memory CD8+ T cells undergo a series of differentiation stages to become fully matured effector cells. There are several important aspects of the current CD8+T cell memory phenotype model that need to be more thoroughly defined.
In specific aim 1, it was hypothesized that CD27+CD28+ undifferentiated CD8+ memory T cells specific for non-persistent virus influenza A (FluA) would have phenotypic markers associated with more differentiated (effector) phenotypes. Results showed that in spite of the phenotypic enrichment of FluA-specific memory CD8+ T cells in the undifferentiated stage, they displayed effector markers indicative of late stage differentiated effector cells.
In specific aim 2, it was further hypothesized that the most undifferentiated CD62L+ central memory CD8+T cells would have the effector function including immediate cytoplasmic production of gamma-IFN upon antigenic-stimulation. Results showed that CD62L+ CD8+ T cells are capable of immediate gamma IFN production after antigen-specific stimulation in the presence of the CD62 sheddase inhibitor, GM6001, highlighting the need to re-evaluate the defining markers of virus-specific central memory CD8+ cells and/or their functions.
In specific aim 3, this dissertation tests the hypothesis that memory-effector differentiation of HIV-1-specific memory CD8+ T cells is impaired during the course of persistent HIV-1 infection. Detailed comparison of CD27 and CD57 co-expression on HIV-1-specific CD8+ T cells showed that these cells had a significantly lower proportion of the CD27CD57high effector subset. Moreover, these cells did not display progression from CD27+CD57 (immature memory), through CD27lowCD57low (transitional memory-effector) to CD27CD57high (effector subset) that was seen in well differentiated EBV-specific CD8+ T cells and was common in CMV-specific CD8+ T cells. These observations suggest that the normal course of HIV-1-specific CD8+ T cell memory-effector differentiation is impaired during the course of persistent HIV-1 infection.
Elucidation of memory-effector differentiation of virus-specific CD8+ T cells has significant public health implications. Understanding the impairment of memory-effector differentiation of HIV-1-specific CD8+ T cells, for instance, will greatly facilitate a design of effective vaccine against progressive HIV-1 infection.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04142005-153607 |
| Date | 09 June 2005 |
| Creators | Hoji, Aki |
| Contributors | Massimo M. Trucco, Phalguni Gupta, Simon M. Barratt-Boyes, Charles R. Rinaldo, Jr., Olivera J. Finn |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04142005-153607/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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