title: EBV-specific CD8+ T cell memory: relationships between epitope specificity, cell phenotype, and immediate effector function.
abstract: 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.
authors.affiliation: Cancer Research Campaign Institute for Cancer Studies, Centre for Immune Regulation, University of Birmingham, Birmingham, United Kingdom.
authors.forename: A D
authors.initials: AD
authors.lastname: Hislop
authors.forename: N H
authors.initials: NH
authors.lastname: Gudgeon
authors.forename: M F
authors.initials: MF
authors.lastname: Callan
authors.forename: C
authors.initials: C
authors.lastname: Fazou
authors.forename: H
authors.initials: H
authors.lastname: Hasegawa
authors.forename: M
authors.initials: M
authors.lastname: Salmon
authors.forename: A B
authors.initials: AB
authors.lastname: Rickinson
mesh_terms: D015415:Biomarkers / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000032:analysis / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000032:analysis / Q000276:immunology; D015795:HLA-B8 Antigen / Q000032:analysis / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D010446:Peptide Fragments / Q000032:analysis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D015795:HLA-B8 Antigen; D010446:Peptide Fragments