by Hoji, Aki

Abstract (Summary)
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.
Bibliographical Information:

Advisor:Massimo M. Trucco; Phalguni Gupta; Simon M. Barratt-Boyes; Charles R. Rinaldo, Jr.; Olivera J. Finn

School:University of Pittsburgh

School Location:USA - Pennsylvania

Source Type:Master's Thesis

Keywords:infectious diseases and microbiology


Date of Publication:06/09/2005

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