Combined experimental and modeling studies reveal new mechanisms in T cell antigen recognition

Rittase, William Russell

Title:

Combined experimental and modeling studies reveal new mechanisms in T cell antigen recognition

dc.contributor.author	Rittase, William Russell
dc.contributor.committeeMember	Kemp, Melissa
dc.contributor.committeeMember	Thomas, Susan
dc.contributor.committeeMember	Sulchek, Todd
dc.contributor.committeeMember	Platt, Manu
dc.contributor.department	Mechanical Engineering
dc.date.accessioned	2018-08-20T15:37:01Z
dc.date.available	2018-08-20T15:37:01Z
dc.date.created	2018-08
dc.date.issued	2018-07-20
dc.date.submitted	August 2018
dc.date.updated	2018-08-20T15:37:01Z
dc.description.abstract	T cells of the immune system recognize small antigen peptide fragments loaded onto Major Histocompatibility Complex (pMHC) molecules through their T Cell Receptor (TCR). The recognition of antigenic pMHC by the TCR is an extremely sensitive and specific process, discriminating as few as a single antigenic pMHC from the self majority while remaining tolerant to uninfected cells. This unique sensitivity and specificity have been intensely studied, but much is still unknown regarding the antigen recognition process. A horizontal atomic force microscope was developed to assist in parsing this unique behavior. Utilizing this system, periods of upregulated adhesion, called TCR ligand memory, were investigated between 1E6 TCR and a panel of pMHC of varying potency under various pharmacological interventions. This behavior was simulated to extract estimates of kinetic parameters and indicated that TCRs quickly upregulate their kinetics several magnitudes upon initial antigen recognition for antigen recapture. Additionally, OT-1 double positive thymocytes were probed by pMHC using a Biomembrane Force Probe (BFP) with different ligands under the presence of CD8, a coreceptor which also binds MHC independently of TCR. Simulations of the BFP assay suggested that mechanotransduction by the TCR resulted in active heterodimerization of CD8 and TCR via intercellular interactions. These results indicate that the binding kinetics of the TCR and associated molecules are not static as previously considered and actively change to enhance recognition. The implications for future research on the TCR and general molecular kinetics are discussed.
dc.description.degree	Ph.D.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/1853/60273
dc.language.iso	en_US
dc.publisher	Georgia Institute of Technology
dc.subject	T cell
dc.subject	Molecular memory
dc.subject	T cell receptor
dc.subject	CD8
dc.subject	Antigen recognition
dc.title	Combined experimental and modeling studies reveal new mechanisms in T cell antigen recognition
dc.type	Text
dc.type.genre	Dissertation
dspace.entity.type	Publication
local.contributor.corporatename	George W. Woodruff School of Mechanical Engineering
local.contributor.corporatename	College of Engineering
relation.isOrgUnitOfPublication	c01ff908-c25f-439b-bf10-a074ed886bb7
relation.isOrgUnitOfPublication	7c022d60-21d5-497c-b552-95e489a06569
thesis.degree.level	Doctoral