title: Dominant human CD8 T cell clonotypes persist simultaneously as memory and effector cells in memory phase.
abstract: The adaptive immune system plays a critical role in protection at the time of secondary infection. It does so through the rapid and robust reactivation of memory T cells which are maintained long-term, in a phenotypically heterogeneous state, following their primary encounter with Ag. Although most HLA-A*0201/influenza matrix protein(58-66)-specific CD8 T cells from healthy donors display characteristics typical of memory T cells, through our extensive phenotypic analysis we have further shown that up to 20% of these cells express neither the IL-7 receptor CD127 nor the costimulatory molecule CD28. In contrast to the majority of CD28(pos) cells, granzyme B and perforin were frequently expressed by the CD28(neg) cells, suggesting that they are effector cells. Indeed, these cells were able to kill target cells, in an Ag-specific manner, directly ex vivo. Thus, our findings demonstrate the remarkable long-term persistence in healthy humans of not only influenza-specific memory cells, but also of effector T cells. We further observed that granzyme B expression in influenza-specific CD8 T cells paralleled levels in the total CD8 T cell population, suggestive of Ag-nonspecific bystander activation. Sequencing of TCR alpha- and beta-chains showed that the TCR repertoire specific for this epitope was dominated by one, or a few, T cell clonotype per healthy donor. Moreover, our sequencing analysis revealed, for the first time in humans, that identical clonotypes can coexist as both memory and effector T cells, thereby supporting the principle of multipotent clonotypic differentiation.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Touvrey
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.forename: Estelle
authors.initials: E
authors.lastname: Devevre
authors.forename: Patricia
authors.initials: P
authors.lastname: Corthesy
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
mesh_terms: D018106:CD28 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002999:Clone Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000032:analysis; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D053699:Interleukin-7 Receptor alpha Subunit / Q000032:analysis; D054353:Perforin / Q000032:analysis
chemical_list: D018106:CD28 Antigens; D053699:Interleukin-7 Receptor alpha Subunit; D054353:Perforin; D053804:Granzymes