title: Peptide ligand structure and I-Aq binding avidity influence T cell signaling pathway utilization.
abstract: Factors that drive T cells to signal through differing pathways remain unclear. We have shown that an altered peptide ligand (A9) activates T cells to utilize an alternate signaling pathway which is dependent upon FcRγ and Syk. However, it remains unknown whether the affinity of peptide binding to MHC drives this selection. To answer this question we developed a panel of peptides designed so that amino acids interacting with the p6 and p9 predicted MHC binding pockets were altered. Analogs were tested for binding to I-A(q) using a competitive binding assay and selected analogs were administered to arthritic mice. Using the collagen-induced arthritis (CIA) model, arthritis severity was correlated with T cell cytokine production and molecular T cell signaling responses. We establish that reduced affinity of interaction with the MHC correlates with T cell signaling through the alternative pathway, leading ultimately to secretion of suppressive cytokines and attenuation of arthritis.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, United States. Electronic address: lmyers@uthsc.edu.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Myers
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Cullins
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Jeoung-Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
authors.forename: Ae-Kyung
authors.initials: AK
authors.lastname: Yi
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Research Service, Veterans Affairs Medical Center, Memphis, TN 38104, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Research Service, Veterans Affairs Medical Center, Memphis, TN 38104, United States.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Rosloniec
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Research Service, Veterans Affairs Medical Center, Memphis, TN 38104, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Stuart
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Research Service, Veterans Affairs Medical Center, Memphis, TN 38104, United States.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kang
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008024:Ligands; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism*; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D024043:Collagen Type II; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell
keywords: Arthritis; Autoimmunity; T cells