Although every T cells recognizes and interacts with self-antigens, it is unknown why only some T cells cause autoimmune disease. HLA class II alleles have been identified as the number one risk factor in MS as well several other autoimmune diseases. Because MHC molecules present peptide antigens to create the antigenic ligand for T cell receptors (TCR), some breakdown in antigen recognition is responsible for autoimmune disease. However, the defects in antigen recognition are unknown. Our work seeks to determine the process of antigen recognition by autoimmune T cells from the CNS by defining the two dimensional (2D) binding kinetics of TCR for myelin peptide:MHC (pMHC). This renewal R01, builds on our published work from the last funding cycle that defined how 2D affinity of myelin oligodendrocyte glycoprotein (MOG)-specific populations related to EAE induction. Now we will determine what dictates the lifetime of antigen recognition. The bond lifetime of TCR interaction with pMHC is a novel and exciting area of research because we, and others, have found that the dynamic activities of T cells apply force to the APC resulting in alteration the length of time of antigen recognition. Importantly, bond lifetime determines T cell activation and dictates their fate - our work and that of others show it is absolutely required for optimal T cell function. Our preliminary data demonstrates that MOG-specific T cells from the CNS have greatly increased bond lifetime as compared to the cells in the periphery. This is in contrast to foreign antigen specific T cells that demonstrate no difference in force induced bond lifetimes on activation. For this renewal application we have generated compelling preliminary data using several unique technologies and animal models. Moreover, we apply these technologies to define the process of self-antigen recognition in the CNS. Together, the proposed work will fully define the bond lifetime under force that occurs between TCR and MOG self-antigens from nave peripheral to active effector T cells in the CNS. The innovative insights generated by continuation of our work will provide the base understanding of T cell activation that permits demyelinating disease. The work will be undertaken through 3 specific aims that will: 1) Define 2D force-induced changes in bond lifetimes during demyelinating disease 2) Define the magnitude and mechanisms by which CD4 T cells generate force 3) Delineate dietary fatty acid impact on TCR:myelin 2D kinetics

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071518-07
Application #
9536147
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2010-06-01
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Blanchfield, Lori; Sabatino Jr, Joseph J; Lawrence, Laurel et al. (2017) NFM Cross-Reactivity to MOG Does Not Expand a Critical Threshold Level of High-Affinity T Cells Necessary for Onset of Demyelinating Disease. J Immunol 199:2680-2691
Martinez, Ryan J; Andargachew, Rakieb; Martinez, Hunter A et al. (2016) Low-affinity CD4+ T cells are major responders in the primary immune response. Nat Commun 7:13848
Shorter, Shayla K; Schnell, Frederick J; McMaster, Sean R et al. (2016) Viral Escape Mutant Epitope Maintains TCR Affinity for Antigen yet Curtails CD8 T Cell Responses. PLoS One 11:e0149582
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Frost, Elizabeth L; Kersh, Anna E; Evavold, Brian D et al. (2015) Cutting Edge: Resident Memory CD8 T Cells Express High-Affinity TCRs. J Immunol 195:3520-4
Hood, Jennifer D; Zarnitsyna, Veronika I; Zhu, Cheng et al. (2015) Regulatory and T Effector Cells Have Overlapping Low to High Ranges in TCR Affinities for Self during Demyelinating Disease. J Immunol 195:4162-70
Martinez, Ryan J; Evavold, Brian D (2015) Lower Affinity T Cells are Critical Components and Active Participants of the Immune Response. Front Immunol 6:468
Hong, Jinsung; Persaud, Stephen P; Horvath, Stephen et al. (2015) Force-Regulated In Situ TCR-Peptide-Bound MHC Class II Kinetics Determine Functions of CD4+ T Cells. J Immunol 195:3557-64
Liu, Baoyu; Chen, Wei; Evavold, Brian D et al. (2014) Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell 157:357-368

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