Rare, structurally homologous self-peptides promote thymocyte positive selection.
Although it is clear that positive selection of T cells involves recognition of specific self-peptide/MHC complexes, the nature of these self-ligands and their relationship to the cognate antigen are controversial. Here we used two complementary strategies to identify naturally occurring self-peptides able to induce positive selection of T cells bearing a specific T cell receptor, OT-I. Both the bioassay- and bioinformatics-based strategies identified the same self-peptides, derived from F-actin capping protein and beta-catenin. These peptides displayed charge conservation at two key TCR contact residues. The biological activity of 43 other self-peptides and of complex peptide libraries directly correlated to the extent of conservation at TCR contact residues. These results demonstrate that selecting self-peptides are rare and can be identified by homology-based search strategies.
Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, 550 First Avenue, NY 10016, USA.
Fabio R
FR
Santori
William C
WC
Kieper
Stuart M
SM
Brown
Yun
Y
Lu
Thomas A
TA
Neubert
Kenneth L
KL
Johnson
Stephen
S
Naylor
Stanislav
S
Vukmanović
Kristin A
KA
Hogquist
Stephen C
SC
Jameson
D051339:Actin Depolymerizing Factors; D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001681:Biological Assay; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000276:immunology*; D051345:Destrin; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000737:chemistry / Q000276:immunology*; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology*; D015534:Trans-Activators / Q000737:chemistry / Q000276:immunology*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D051339:Actin Depolymerizing Factors; D001324:Autoantigens; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D051345:Destrin; D008840:Microfilament Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators; D051176:beta Catenin