EBV-Specific CD8+ T cell memory:: Relationships between epitope specificity, cell phenotype, and immediate effector function

EBV infection in humans induces CD8(+) T cell memory to viral epitopes derived from both lytic and latent cycle Ags. We have analyzed the relationship between the phenotype and function of the memory pool of T cells specific for these Ags. Lytic epitope-specific populations were heterogeneous in terms of CD45RO/RA and CD28 expression, whereas latent epitope-specific populations were uniformly CD45RO(+) and CD28(+), consistent with the higher antigenic challenge from lytic epitopes driving some memory cells toward a CD45RA(+), CD28(-) phenotype. However, both types of memory population showed immediate epitope-specific cytotoxicity and type 1 cytokine production in ex vivo assays. Cytotoxic function was not associated with preactivated T cells, as EBV-specific populations were negative for activation markers such as CD69 or CD38, nor could cytotoxic function be ascribed to CD27(-) or CD56(+) subsets, as such cells were not detected in EBV-specific memory. Furthermore, cytotoxicity was not limited to CD45RA(+) and/or CD28(-) fractions, but also was observed in CD45RO(+), CD28+ populations in lytic and latent epitope-specific memory. Cytokine (IFN-gamma, TNF-alpha) responses, measured by intracytoplasmic staining after peptide stimulation, also were detectable in CD45RO+ and RA(+) subsets as well as CD28(+) and CD28- subsets. Of other markers that were heterogeneous in both lytic and latent epitope populations, CCR7 gave the best discrimination of functionality; thus, CCR7(+) cells consistently failed to give an IFN-gamma or TNF-alpha response, whereas many CCR7(-) cells were responsive. Our data are consistent with effector functions having a broad distribution among phenotypically distinct subsets of effector memory cells that have lost the CCR7 marker. The Journal of Immunology, 2001.