title: Avidity maturation of memory CD8 T cells is limited by self-antigen expression.
abstract: Immune tolerance to self-antigens is a complex process that utilizes multiple mechanisms working in concert to maintain homeostasis and prevent autoimmunity. We developed a system that revealed a population of self-specific CD8 T cells within the endogenous T cell repertoire. Immunization of ovalbumin (OVA)-expressing transgenic mice with recombinant viruses expressing OVA-peptide variants induced self-reactive T cells in vivo that matured into memory T cells able to respond to secondary infection. However, whereas the avidity of memory cells in normal mice increased dramatically with repeated immunizations, avidity maturation was limited for self-specific CD8 T cells. Despite decreased avidity, such memory cells afforded protection against infection, but did not induce overt autoimmunity. Further, up-regulation of self-antigen expression in dendritic cells using an inducible system promoted programmed death-1 expression, but not clonal expansion of preexisting memory cells. Thus, the self-reactive T cell repertoire is controlled by overlapping mechanisms influenced by antigen dose.
authors.affiliation: Department of Immunology, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Turner
authors.forename: Evan R
authors.initials: ER
authors.lastname: Jellison
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Lingenheld
authors.forename: Lynn
authors.initials: L
authors.lastname: Puddington
authors.forename: Leo
authors.initials: L
authors.lastname: Lefrançois
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D003429:Cross Reactions; D005260:Female; D007108:Immune Tolerance; D007156:Immunologic Memory; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D017634:Self Tolerance; D014157:Transcription Factors / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D010047:Ovalbumin; D010446:Peptide Fragments; D014157:Transcription Factors; D000096927:AIRE Protein; C110366:OVA-8