title: Positive selection optimizes the number and function of MHCII-restricted CD4+ T cell clones in the naive polyclonal repertoire.
abstract: T cell receptors (TCRs) on T lymphocytes in an individual bind foreign peptides bound to major histocompatibility complex (MHC) molecules expressed in that individual (designated MHC(A)). Results from radiation bone marrow chimeras and TCR transgenic mice indicate that this complex form of antigen recognition is the result of positive selection of clones with low affinity for self peptide:MHC(A) complexes during development. Here we used a sensitive peptide:MHC tetramer enrichment method to quantify the role of positive selection in the generation of the preimmune polyclonal T cell repertoire in normal individuals. We made the surprising observation that mouse and human naive T cells capable of binding to foreign peptide:MHC(A) were present at the same frequency in hosts that expressed MHC(A) or a different MHC isoform (MHC(B)). However, most of the clones in MHC(B) hosts also recognized self peptide:MHC(A) complexes. When these "alloreactive" T cells were removed from the MHC(B) repertoire via negative selection in an MHC(A) host, the number of foreign peptide:MHC(A)-binding T cells was reduced to one fifth and many of the remaining cells did not respond to the peptide. Therefore, although positive selection on MHC(A) was not required to produce foreign peptide:MHC(A)-binding clones, it had a large effect on selecting responsive clones.
authors.affiliation: Department of Microbiology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: H Hamlet
authors.initials: HH
authors.lastname: Chu
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.forename: Kensuke
authors.initials: K
authors.lastname: Takada
authors.forename: Marion
authors.initials: M
authors.lastname: Pepper
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Molitor
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Schacker
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Hogquist
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Jameson
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002678:Chimera / Q000276:immunology; D002999:Clone Cells; D003433:Crosses, Genetic; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology; D012641:Selection, Genetic
chemical_list: D000949:Histocompatibility Antigens Class II; D010455:Peptides