Differential activation of human autoreactive T cell clones by altered peptide ligands derived from myelin basic protein peptide (87-99).
We have examined the functional consequences induced by interaction of DR2a-restricted myelin basic protein (MBP) (87-99)-specific T cell clones (TCC) with altered peptide ligands (APL) derived from MBP peptide (87-99). The immunodominant MBP peptide (87-99) has been implicated as a candidate antigen in multiple sclerosis (MS) by several lines of evidence. In the present study, we have defined the T cell receptor (TCR) contact residues for DR2a-restricted, (87-99)-specific T helper type 1 T cells to design APL suitable to modify the functions of such T cells potentially relevant for the pathogenesis of MS. We show that neutral (L-alanine substitutions) or conservative exchanges of the primary and secondary TCR contact residues lead to various alterations of T cell function, ranging from differences in interleukin-2 receptor up-regulation to anergy induction and TCR antagonism. The potential usefulness of APL as an immunomodulating therapy for DR2+ MS patients is discussed.
Vergelli
M
M
Neuroimmunology Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
Hemmer
B
B
Utz
U
U
Vogt
A
A
Kalbus
M
M
Tranquill
L
L
Conlon
P
P
Ling
N
N
Steinman
L
L
McFarland
H F
HF
Martin
R
R
D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D002999:Clone Cells; D015802:HLA-DR2 Antigen / Q000235:genetics; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; D015802:HLA-DR2 Antigen; D008024:Ligands; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell