title: Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors.
abstract: The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC.
authors: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;
authors: Daniel
authors: D
authors: Silberman
authors: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;
authors: Sai Harsha
authors: SH
authors: Krovi
authors: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;
authors: Kathryn D
authors: KD
authors: Tuttle
authors: Division of Biostatistics and Bioinformatics, National Jewish Health, Denver, CO 80206;
authors: James
authors: J
authors: Crooks
authors: Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO 80045;
authors: Richard
authors: R
authors: Reisdorph
authors: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;
authors: Janice
authors: J
authors: White
authors: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;
authors: James
authors: J
authors: Gross
authors: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;
authors: Jennifer L
authors: JL
authors: Matsuda
authors: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045;
authors: Laurent
authors: L
authors: Gapin
authors: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045; Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206 marrackp@njhealth.org kapplerj@njhealth.org.
authors: Philippa
authors: P
authors: Marrack
authors: Department of Biomedical Research, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045; Howard Hughes Medical Institute, National Jewish Health, Denver, CO 80206 marrackp@njhealth.org kapplerj@njhealth.org.
authors: John W
authors: JW
authors: Kappler
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D005854:Germ Cells / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D051379:Mice; D010455:Peptides / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: MHC; T-cell receptor; evolution; mutation; variable region