title: Preferential escape of subdominant CD8+ T cells during negative selection results in an altered antiviral T cell hierarchy.
abstract: Negative selection is designed to purge the immune system of high-avidity, self-reactive T cells and thereby protect the host from overt autoimmunity. In this in vivo viral infection model, we show that there is a previously unappreciated dichotomy involved in negative selection in which high-avidity CD8(+) T cells specific for a dominant epitope are eliminated, whereas T cells specific for a subdominant epitope on the same protein preferentially escape deletion. Although this resulted in significant skewing of immunodominance and a substantial depletion of the most promiscuous T cells, thymic and/or peripheral deletion of high-avidity CD8(+) T cells was not accompanied by any major change in the TCR V beta gene family usage or an absolute deletion of a single preferred complementarity-determining region 3 length polymorphism. This suggests that negative selection allows high-avidity CD8(+) T cells specific for subdominant or cryptic epitopes to persist while effectively deleting high-avidity T cells specific for dominant epitopes. By allowing the escape of subdominant T cells, this process still preserves a relatively broad peripheral TCR repertoire that can actively participate in antiviral and/or autoreactive immune responses.
authors.affiliation: Oregon Health and Science University Vaccine and Gene Therapy Institute, Beaverton, OR 97006, USA.
authors.forename: Mark K
authors.initials: MK
authors.lastname: Slifka
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Blattman
authors.forename: David J D
authors.initials: DJ
authors.lastname: Sourdive
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Donald L
authors.initials: DL
authors.lastname: Huffman
authors.forename: Tom
authors.initials: T
authors.lastname: Wolfe
authors.forename: Anna
authors.initials: A
authors.lastname: Hughes
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.forename: Matthias G
authors.initials: MG
authors.lastname: Von Herrath
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D016056:Immunodominant Epitopes / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D005810:Multigene Family / Q000276:immunology; D009698:Nucleoproteins / Q000096:biosynthesis / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D009698:Nucleoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014764:Viral Proteins