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dc.contributor.advisorZhu, Cheng
dc.contributor.authorHong, Jin Sung
dc.date.accessioned2015-06-08T18:10:57Z
dc.date.available2015-06-09T05:30:06Z
dc.date.created2014-05
dc.date.issued2014-03-31
dc.date.submittedMay 2014
dc.identifier.urihttp://hdl.handle.net/1853/53430
dc.description.abstractT cell activation and thymic selection are thought to be determined by the binding propensity (avidity or affinity) of the T cell receptor (TCR) to its ligands. However, binding propensity quantified by previous 3D TCR–pMHC kinetics such as using tetramer staining or surface plasmon resonance (SPR) under estimate TCR–pMHC interaction due to neglecting physiological conditions. Recent studies considering membrane contribution in TCR–pMHC interaction reported 2D kinetics and force regulated bond dissociation kinetics have better prediction to biological responses in CD8+ T cells. In this study, we further tested the findings in CD4+ T cells and CD4+ CD8+ (double-positive, DP) thymocytes. We analyzed TCR–pMHC interaction for a well-characterized panel of altered peptide ligands (APLs) on multiple transgenic mouse TCR systems. Using ultrasensitive 2D mechanical assays, in situ 2D kinetic measurements show better sensitivity than the SPR 3D kinetic measurements in gauging the ligand potency and thymic selection. Furthermore, force-regulated bond lifetime of TCR–pMHC interaction amplifies the discrimination in recognition of APLs and thymic selection. When force was applied to TCR–pMHC–CD4/8 bonds, two distinct patterns emerged: agonist/negative selecting ligands formed CD4/8-dependent catch-slip bonds where lifetime first increased, reached a maximum, then decreased with increasing force, whereas antagonist/positive selecting ligands formed slip-only bonds where lifetime monotonically decreases with increasing force. Our results highlight an important role of mechanical force in ligand discrimination and suggest a new mechanism for T cell activation and thymic selection that is distinct from previous models based on 3D measurements.
dc.format.mimetypeapplication/pdf
dc.language.isoen_US
dc.publisherGeorgia Institute of Technology
dc.subjectT cell recognition
dc.subjectT cell activation
dc.subjectThymic selection
dc.subjectTCR-pMHC interaction
dc.subjectCo-receptor cooperativity
dc.subject2D kinetics
dc.subjectCatch bond
dc.titleStudy of 2D kinetics and force regulation in T cell recognition
dc.typeDissertation
dc.description.degreePh.D.
dc.contributor.departmentMechanical Engineering
dc.embargo.terms2015-05-01
thesis.degree.levelDoctoral
dc.contributor.committeeMemberGarcía, Andrés
dc.contributor.committeeMemberBabensee, Julia
dc.contributor.committeeMemberKemp, Melissa
dc.contributor.committeeMemberEvavold, Brian
dc.date.updated2015-06-08T18:10:57Z


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