CDR3 sequence preference of TCRBV8S2+ T cells within the CNS does not reflect single amino acid dependent avidity expansion.
To investigate the influence of antigen and restricting MHC class II molecule on the T cell repertoire, we varied the peptide source by immunizing either with myelin basic protein (MBP) (rat)63-88 or MBP(GUINEA PIG (GP))63-88, which differ in the core region of the peptide binding site at position 79 by a single exchange of threonine (T) to serine (S) and by altering the MHC by immunizing MHC congenic LEW (RT1(1)) and LEW.1W (RT1u) rats. In both MHC haplotypes both peptides lead to oligoclonal dominance of TCRBV8S2 expressing T cells within the central nervous system (CNS) as assessed by complementary determining region 3 (CDR3) spectratyping. In contrast cytofluorometric analysis indicated that only MBP(GP)63-88 in context with the RT1(l) haplotype of the LEW rat lead to strong expansions of TCRBV8S2 expressing T cells within the CNS. Importantly, the small conservative change from S to T at position 79 within MBP63-88 had a strong influence both on the encephalitogenic potential of the peptide and on the number of TCRBV8S2+ T cells infiltrating the CNS. These results demonstrate that even minor changes in only one side chain of an amino acid within an (auto)antigen can dramatically alter TCR avidity for certain MHC class II/peptide complexes.
de Graaf
Katrien L
KL
Experimental Neuroimmunology Laboratory, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
Berne
Gabrielle Paulsson
GP
Herrmann
Martin M
MM
Hansson
Göran K
GK
Olsson
Tomas
T
Weissert
Robert
R
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002455:Cell Division; D002469:Cell Separation; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D022801:Complementarity Determining Regions; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D005434:Flow Cytometry; D006168:Guinea Pigs; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D007114:Immunization; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000378:metabolism*; D012694:Serine; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D013912:Threonine
D022801:Complementarity Determining Regions; D000949:Histocompatibility Antigens Class II; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C503720:myelin basic protein 63-88; D013912:Threonine; D012694:Serine