Peptide ligand structure and I-Aq binding avidity influence T cell signaling pathway utilization

- We propose a therapy in which peptides induce inhibitory T cells.
- The avidity of interaction of peptide with MHC determines the T cell signaling pathway.
- These studies will lead to safer peptide-based therapies for autoimmunity.

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-Aq 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.