title: Functional avidity-driven activation-induced cell death shapes CTL immunodominance.
abstract: Immunodominance is a complex phenomenon that relies on a mere numerical concept, while being potentially influenced at every step of the immune response. We investigated the mechanisms leading to the establishment of CTL immunodominance in a retroviral model and found that the previously defined subdominant Env-specific CD8(+) T cells are endowed with an unexpectedly higher functional avidity than is the immunodominant Gag-recognizing counterpart. This high avidity, along with the Env Ag overload, results in a supraoptimal TCR engagement. The overstimulation makes Env-specific T lymphocytes more susceptible to apoptosis, thus hampering their expansion and leading to an unintentional "immune kamikazing." Therefore, Ag-dependent, hyperactivation-induced cell death can be regarded as a novel mechanism in the establishment of the immunodominance that restrains and opposes the expansion of high-avidity T cells in favor of lower-affinity populations.
authors.affiliation: Veneto Institute of Oncology, 35128 Padua, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Dalla Santa
authors.affiliation: Veneto Institute of Oncology, 35128 Padua, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: Merlo
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Biopôle III, 1066 Epalinges, Lausanne, Switzerland;
authors.forename: Sara
authors.initials: S
authors.lastname: Bobisse
authors.affiliation: Excellence Centre for Research, Transfer, and High Education, University of Florence, 50139 Florence, Italy;
authors.forename: Elisa
authors.initials: E
authors.lastname: Ronconi
authors.affiliation: Veneto Institute of Oncology, 35128 Padua, Italy;
authors.forename: Daniela
authors.initials: D
authors.lastname: Boldrin
authors.affiliation: Department of Medicine, University of Padua, 35128 Padua, Italy;
authors.forename: Gabriella
authors.initials: G
authors.lastname: Milan
authors.affiliation: Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy;
authors.forename: Vito
authors.initials: V
authors.lastname: Barbieri
authors.affiliation: Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy;
authors.forename: Oriano
authors.initials: O
authors.lastname: Marin
authors.affiliation: Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy;
authors.forename: Antonella
authors.initials: A
authors.lastname: Facchinetti
authors.affiliation: Department of Molecular Pathology, University of Marche, 60126 Ancona, Italy; and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Biasi
authors.affiliation: National Cancer Institute, 33081 Aviano, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
authors.affiliation: Veneto Institute of Oncology, 35128 Padua, Italy; Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.affiliation: Veneto Institute of Oncology, 35128 Padua, Italy; Department of Surgery, Oncology, and Gastroenterology, University of Padua, 35128 Padua, Italy; antonio.rosato@unipd.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D005260:Female; D015686:Gene Products, env / Q000276:immunology; D015683:Gene Products, gag / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D012190:Retroviridae / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D015686:Gene Products, env; D015683:Gene Products, gag; D016056:Immunodominant Epitopes