title: The expansion and maintenance of antigen-selected CD8(+) T cell clones.
abstract: The biological purpose of the mature, postthymic CD8(+) T cell is to respond to microbial antigens with a developmental program of clonal expansion and concomitant differentiation leading to effector cells (T(EFF)) that provide antimicrobial defense. Because many microbial infections persist into a chronic phase, this antigen-stimulated developmental program must be capable of continually generating T(EFF), perhaps for the lifetime of the individual. This chapter proposes that the ability of a CD8(+) T cell clone to maintain the continual production of T(EFF) during periods of persistent antigenic stimulation is based on a program that has two sequential phases of clonal expansion: an initial stage that occurs mainly in the secondary lymphoid tissues and is mediated by ligation of the T cell receptor (TCR) and CD27, and a subsequent, IL-2-dependent phase that occurs predominantly in peripheral, nonlymphoid tissues. The TCR/CD27-dependent phase establishes a nondifferentiating, self-renewing pool of clonally expanding cells, and the IL-2-dependent phase mediates continued clonal expansion that is coupled to the development of T(EFF). The two pools are linked by the process of asymmetrical division within the self-renewing subset so that, at steady state of cellular replication in this TCR/CD27-dependent subset, one daughter cell remains undifferentiated and the other initiates its commitment to IL-2-dependent terminal differentiation. Superimposed on this basic scheme are a shift in the CD8(+) T cell response to type I and II interferon (IFN) from anti- to pro-proliferative and transcriptional control of replicative senescence by Bmi-1, Blimp-1, and BCL6/BCL6b. This developmental program ensures that despite the occurrence of cellular senescence antiviral CD8(+) T cell clones are maintained for the duration of persistent viral infections.
authors.affiliation: Wellcome Trust Immunology Unit, University of Cambridge, Medical Research Council Centre, Cambridge CB2 2QH, United Kingdom.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Fearon
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D002454:Cell Differentiation; D002999:Clone Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D007372:Interferons / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000276:immunology / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D007376:Interleukin-2; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D007372:Interferons