Functional evidence for the recognition of endogenous peptides by autoreactive T cell clones.
The fine specificity of two human T cell clones responding to autologous HLA-DR1 expressing antigen-presenting cells (APC) in the absence of nominal antigen has been investigated using Epstein-Barr virus-transformed B cells (BCL) of known DR beta 1 domain sequence. It was found that responsiveness was markedly affected by changes in a limited number of residues in this domain. Substitution of the DR1 beta sequence at one residue, position 74, even conservatively, was found to be particularly significant. Located on the beta 1 domain alpha-helix, this residue is predicted to point into the antigen-binding groove and is therefore unlikely to make contact with the T cell receptor. This finding suggests that these T cells are specific for a bound endogenous peptide within the autologous major histocompatibility (MHC) binding groove. The autospecific T cell clones also responded to murine L cell transfectants expressing DR alpha DR1 beta as well as to transfectants expressing the mouse/human hybrid MHC molecule I-E alpha DR1 beta but not to the reciprocal combination DR alpha I-E beta, thus confirming the importance of the beta 1 domain to T cell recognition. In contrast to the autocytotoxicity observed with BCL, cytolysis of the murine L cells expressing the HLA-DR1 molecule was slight and only found at high effector-target ratios. In addition, although fixation enhanced the recognition of BCL, capacity of the murine L cells bearing the HLA-DR1 molecule to stimulate T cell clone proliferation was markedly reduced by aldehyde fixation. When taken together, these results suggest that the endogenous peptides recognized by these autoreactive T cells are of human origin.
Rees
A D
AD
MRC Tuberculosis and Related Infections Unit, Hammersmith Hospital, London, UK.
Lombardi
G
G
Scoging
A
A
Barber
L
L
Mitchell
D
D
Lamb
J
J
Lechler
R
R
D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry; D015704:CD4 Antigens; D002999:Clone Cells / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D015798:HLA-DR1 Antigen / Q000737:chemistry; D006801:Humans; D007739:L Cells / Q000276:immunology; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D015704:CD4 Antigens; D015798:HLA-DR1 Antigen; D010455:Peptides