title: Molecular basis for T cell response induced by altered peptide ligand of type II collagen.
abstract: Mounting evidence from animal models has demonstrated that alterations in peptide-MHC interactions with the T cell receptor (TCR) can lead to dramatically different T cell outcomes. We have developed an altered peptide ligand of type II collagen, referred to as A9, which differentially regulates TCR signaling in murine T cells leading to suppression of arthritis in the experimental model of collagen-induced arthritis. This study delineates the T cell signaling pathway used by T cells stimulated by the A9·I-A(q) complex. We have found that T cells activated by A9 bypass the requirement for Zap-70 and CD3-ζ and signal via FcRγ and Syk. Using collagen-specific T cell hybridomas engineered to overexpress either Syk, Zap-70, TCR-FcRγ, or CD3-ζ, we demonstrate that A9·I-A(q) preferentially activates FcRγ/Syk but not CD3-ζ/Zap-70. Moreover, a genetic absence of Syk or FcRγ significantly reduces the altered peptide ligand induction of the nuclear factor GATA3. By dissecting the molecular mechanism of A9-induced T cell signaling we have defined a new alternate pathway that is dependent upon FcRγ and Syk to secrete immunoregulatory cytokines. Given the interest in using Syk inhibitors to treat patients with rheumatoid arthritis, understanding this pathway may be critical for the proper application of this therapy.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Jeoung-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: David
authors.initials: D
authors.lastname: Cullins
authors.forename: Lillian
authors.initials: L
authors.lastname: Zalduondo
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Barnett
authors.forename: Ae-Kyung
authors.initials: AK
authors.lastname: Yi
authors.forename: Sandra
authors.initials: S
authors.lastname: Kleinau
authors.forename: John M
authors.initials: JM
authors.lastname: Stuart
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kang
authors.forename: Linda K
authors.initials: LK
authors.lastname: Myers
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D017252:CD3 Complex / Q000235:genetics; D024043:Collagen Type II / Q000276:immunology* / Q000494:pharmacology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D017252:CD3 Complex; C485468:Cd3e protein, mouse; D024043:Collagen Type II; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D011961:Receptors, Fc; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse