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Michael A Faust, Elizabeth M Kolawole, Brian D Evavold, MOG variant 45D does not properly activate high-affinity, MOG reactive effector T cells but allows for high-affinity FoxP3+ Treg function, The Journal of Immunology, Volume 208, Issue Supplement_1, May 2022, Page 60.19, https://doi.org/10.4049/jimmunol.208.Supp.60.19
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Abstract
Although it’s well appreciated that autoreactive T cells can drive autoimmune disease, how T cells precisely distinguish and respond to epitopes is unclear. For example, T cells can proliferate in response to multiple epitopes of myelin oligodendrocyte glycoprotein (MOG), but not all epitopes are encephalitogenic. Here, we investigate why T cells specific for MOG 35–55 are encephalitogenic. We compare the wildtype MOG epitope (wtMOG) to a single amino acid substitute, 45D, which was engineered to expresses the same T cell receptor (TCR) contact residues as wtMOG but is mutated such that its affinity for MHC II is decreased. We employed the micropipette adhesion frequency assay to demonstrate that a monoclonal, MOG-specific, high-affinity TCR binds to 45D with the same affinity as wtMOG. Despite conserved TCR contact residues, the MOG 45D variant is not encephalitogenic and fails to prime high-affinity tetramer-positive TCR clones. We also extended our polyclonal analysis to FoxP3+ regulatory T cells (Tregs) and found that, compared to wtMOG, 45D priming increases the frequency of MOG-specific Tregs. We further show that these Tregs are functional and suppress the proliferation of MOG-specific T cells. Our work begins to dissect the differential T cell receptor kinetic properties that allow for a response, or lack thereof, in Tregs and Teffs to myelin peptides.
Supported by NIH R01 NS071518-09
