title: Membrane association of the CD3ε signaling domain is required for optimal T cell development and function.
abstract: The TCR:CD3 complex transduces signals that are critical for optimal T cell development and adaptive immunity. In resting T cells, the CD3ε cytoplasmic tail associates with the plasma membrane via a proximal basic-rich stretch (BRS). In this study, we show that mice lacking a functional CD3ε-BRS exhibited substantial reductions in thymic cellularity and limited CD4- CD8- double-negative (DN) 3 to DN4 thymocyte transition, because of enhanced DN4 TCR signaling resulting in increased cell death and TCR downregulation in all subsequent populations. Furthermore, positive, but not negative, T cell selection was affected in mice lacking a functional CD3ε-BRS, which led to limited peripheral T cell function and substantially reduced responsiveness to influenza infection. Collectively, these results indicate that membrane association of the CD3ε signaling domain is required for optimal thymocyte development and peripheral T cell function.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105;
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Bettini
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105;
authors.forename: Clifford
authors.initials: C
authors.lastname: Guy
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105;
authors.forename: Pradyot
authors.initials: P
authors.lastname: Dash
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105;
authors.forename: Kate M
authors.initials: KM
authors.lastname: Vignali
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102; and.
authors.forename: David E
authors.initials: DE
authors.lastname: Hamm
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dobbins
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Etienne
authors.initials: E
authors.lastname: Gagnon
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105;
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105; dvignali@pitt.edu.
authors.forename: Dario A A
authors.initials: DA
authors.lastname: Vignali
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology*; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D017252:CD3 Complex; C485468:Cd3e protein, mouse; D011948:Receptors, Antigen, T-Cell