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: Linda K Myers, David L Cullins, Jeoung-Eun Park, Ae-Kyung Yi, David D Brand, Edward F Rosloniec, John M Stuart, Andrew H Kang
• Journal: Clinical immunology (Orlando, Fla.) (Clin Immunol) Vol. 160 Issue 2 Pg. 188-97 (Oct 2015) ISSN: 1521-7035 [Electronic] United States
• PMID: 25982319 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Collagen Type II
• Cytokines
• Histocompatibility Antigens Class II
• Ligands
• Peptide Fragments
• Peptides
• Receptors, Antigen, T-Cell

Topics

• Animals
• Arthritis, Experimental (immunology)
• Collagen Type II (immunology)
• Cytokines (immunology)
• Histocompatibility Antigens Class II (immunology)
• Ligands
• Mice
• Peptide Fragments (immunology, metabolism)
• Peptides (immunology, metabolism)
• Protein Binding
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Severity of Illness Index
• Signal Transduction (immunology)
• T-Lymphocytes (immunology)