| 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 IFN-gamma upon antigenic-stimulation. Results showed that CD62L+CD8 + T cells are capable of immediate IFN-gamma 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 CD27- CD57high effector subset. Moreover, these cells did not display progression from CD27+CD57- (immature memory), through CD27lowCD57low (transitional memory-effector) to CD27-CD57high (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. |
