title: Affinity of thymic self-peptides for the TCR determines the selection of CD8(+) T lymphocytes in the thymus.
abstract: Experiments with synthetic antigen peptides have suggested that a critical parameter that determines the developmental fate of an immature thymocyte is the affinity of interaction between TCR and self-peptide/MHC expressed on thymic stromal cells. To test the physiological relevance of this model for thymocyte development, we determined the affinity of the anti-HY TCR (B6.2.16) expressed on CD8(+) cells for thymic self-peptide/H-2D(b) tetramers, then examined the ability of these self-peptides to determine the outcome of B6.2.16 CD8 cell selection in the thymus. The B6.2.16 TCR bound the male HY self-antigen with high affinity. Thymic self-peptides, which are highly abundant on the surface of thymic epithelial cells, bound the B6.2.16 TCR with low affinity. The ability of self-peptides to trigger positive or negative selection of B6.2.16 CD8 cells in cultured fetal thymi was determined by the relative affinity of self-peptide/H-2D(b) for the B6.2.16 TCR. High-affinity binding of the HY self-peptide resulted in B6.2.16 TCR complex zeta chain phosphorylation and the negative selection of B6.2.16 CD8 cells. Low-affinity binding of thymic self-peptides to B6.2.16 TCR resulted in the positive selection of B6.2.16 CD8 cells. Differences between the binding affinities of self-peptides to B6.2.16 TCR accounted for the self-peptide specificity of B6.2.16 CD8 cell positive selection. We conclude that the relative affinity of TCR for thymic self-peptide/class I MHC is a critical parameter in determining fate of CD8(+) cells during thymic selection.
authors.affiliation: Department of Pathology, University of Chicago, 924 E. 57th Street, R414, IL 60637, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Ober
authors.forename: Q
authors.initials: Q
authors.lastname: Hu
authors.forename: J T
authors.initials: JT
authors.lastname: Opferman
authors.forename: S
authors.initials: S
authors.lastname: Hagevik
authors.forename: N
authors.initials: N
authors.lastname: Chiu
authors.forename: C R
authors.initials: CR
authors.lastname: Wang
authors.forename: P G
authors.initials: PG
authors.lastname: Ashton-Rickardt
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001324:Autoantigens / Q000276:immunology* / Q000302:isolation & purification; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D005333:Fetus; D006183:H-2 Antigens; D006182:H-Y Antigen; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000276:immunology* / Q000302:isolation & purification; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D001324:Autoantigens; D006183:H-2 Antigens; D006182:H-Y Antigen; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C073119:TAP1 protein, human; C486171:Tap1 protein, mouse