title: αβ T cell receptor germline CDR regions moderate contact with MHC ligands and regulate peptide cross-reactivity.
abstract: αβ T cells respond to peptide epitopes presented by major histocompatibility complex (MHC) molecules. The role of T cell receptor (TCR) germline complementarity determining regions (CDR1 and 2) in MHC restriction is not well understood. Here, we examine T cell development, MHC restriction and antigen recognition where germline CDR loop structure has been modified by multiple glycine/alanine substitutions. Surprisingly, loss of germline structure increases TCR engagement with MHC ligands leading to excessive loss of immature thymocytes. MHC restriction is, however, strictly maintained. The peripheral T cell repertoire is affected similarly, exhibiting elevated cross-reactivity to foreign peptides. Our findings are consistent with germline TCR structure optimising T cell cross-reactivity and immunity by moderating engagement with MHC ligands. This strategy may operate alongside co-receptor imposed MHC restriction, freeing germline TCR structure to adopt this novel role in the TCR-MHC interface.
authors: Section of Molecular Immunology, Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
authors: Meriem
authors: M
authors: Attaf
authors: Section of Molecular Immunology, Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
authors: Stephan J
authors: SJ
authors: Holland
authors: Section of Molecular Immunology, Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
authors: Istvan
authors: I
authors: Bartok
authors: Section of Molecular Immunology, Department of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
authors: Julian
authors: J
authors: Dyson
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D003429:Cross Reactions; D005260:Female; D006649:Histocompatibility Antigens / Q000378:metabolism*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics* / Q000276:immunology
chemical_list: D022801:Complementarity Determining Regions; D006649:Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta