Th1 and Th2 deviation of myelin-autoreactive T cells by altered peptide ligands is associated with reciprocal regulation of Lck, Fyn, and ZAP-70.
Th0 clones recognizing an immunodominant peptide of myelin basic protein (residues 83-99) were derived from patients with multiple sclerosis. We demonstrate that analogue peptides with alanine substitution at Val86 and His88 had a unique partial agonistic property in inducing Th0 -->Th1 and Th0 -->Th2 deviation of the myelin basic protein-reactive T cell clones, respectively. Th0 to Th1 deviation induced by peptide 86V-->A correlated with up-regulation of Fyn and ZAP-70 kinase activities. Conversely, Th0 to Th2 deviation induced by peptide 88H-->A was associated with complete failure to activate Fyn and ZAP-70 kinases. The observed Th1 and Th2 shift also correlated, to a lesser extent, with Lck kinase activity that was down-regulated with Th1 deviation and increased with Th2 deviation in some T cell clones. We demonstrated that the Th1 and Th2 shift induced by the analogue peptides was a reversible process, as the T cell clones previously exposed to either 86V-->A or 88H-->A peptide could revert to an opposite phenotype when rechallenged reciprocally with a different analogue peptide. The study has important implications in our understanding of regulation of TCR-associated tyrosine kinases by altered peptide ligands and its role in cytokine regulation of autoreactive T cells.
Singh
R A
RA
Multiple Sclerosis Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
Zang
Y C
YC
Shrivastava
A
A
Hong
J
J
Wang
G T
GT
Li
S
S
Tejada-Simon
M V
MV
Kozovska
M
M
Rivera
V M
VM
Zhang
J Z
JZ
D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology; D002999:Clone Cells; D004789:Enzyme Activation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D010455:Peptides; D011518:Proto-Oncogene Proteins; C104448:myelin basic protein 83-99; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D000409:Alanine