COMBINED EXPERIMENTAL AND MODELING STUDIES REVEAL NEW MECHANISMS IN T CELL ANTIGEN RECOGNITION
- Project Research
- 1-5 Chapters
- Abstract : Available
- Table of Content: Available
- Reference Style: APA
- Recommended for : Student Researchers
- NGN 3000
SUMMARY
T cells of the immune system recognize small antigen peptide fragments loaded onto Major Histocompatibility Complex (MHC) 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 mechanisms surrounding the antigen recognition process. In the following studies, a Horizontal Atomic Force Microscope (HAFM) 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. The strength of these periods of upregulated adhesion, indicative of an upregulated sensitivity to antigen, inversely correlated with antigen potency. Inhibition of proximal signaling molecule Lck decreased the triggering of these periods, but did not significantly affect their duration. Interestingly, membrane cholesterol oxidation by cholesterol oxidase eliminated TCR ligand memory all together. Treatment with cholesterol sulfate, a naturally occurring analog of cholesterol, depleted TCR ligand memory in a dose-dependent fashion. This behavior was simulated to extract estimates of kinetic parameters and showed that TCRs upregulated their kinetics several magnitudes very quickly upon initial antigen recognition. This mechanism is a way to increase antigenic sensitivity and increase antigen rebinding to further cell activation. xiv 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. Negatively selecting ligands resulted in catch-bonds, and positively selecting ligands resulted in slip bonds. This process relied on the kinase activity of Lck. Simulation-based analysis on these data sets indicated that this mechanism was not the result of passive processes. Force induced formation of long-lived bonds, indicating that mechanical forces are priming formation of a larger complex which enhances lifetime. These bonds dominate the average lifetime and result in catch-bond behavior. Simulations of the BFP assay suggest that mechanotransduction by the TCR resulted in active heterodimerization of CD8 and TCR via interactions between intracellular tails of CD3(TCR) and Lck(CD8). This mechanism results in additional upregulation of binding kinetics for increasing antigen capture and rebinding to promote signaling, thereby also increasing antigen sensitivity and discrimination.
Related Project Materials
LOCAL GOVERNMENT AND COMMUNITY DEVELOPMENT
ABSTRACT
This research entitled local Government and community development: A case study of Owerri Muni...
PRACTICAL AND LIGHTWEIGHT DEFENSE AGAINST WEBSITE FINGERPRINTING
ABSTRACT
Website fingerprinting is a passive network traffic analysis technique which enables an adversary to identify the website a user...
TIMELY RELEASE OF RESULTS AND ACADEMIC PERFOMENCE OF STUDENTS IN BUSINESS EDUCATION
ABSTRACT
The research provides an appraisal of timely release of result and its effect on academic performance of&n...
INFLUENCE OF COMMUNITY RADIO IN AGRICULTURAL DEVELOPMENT IN ENUGU STATE.
Background of the Study
In every society we find ourselves, the need for the rules to reach out improve the standard of the ruled is impe...
AN EVALUATION OF GREEN HUMAN RESOURCES AND EMPLOYEES' BEHAVIOR IN HOTEL INDUSTRY
Background Of The Study
Green management has grown in popularity among industry and academia as a way t...
A CRITICAL EXAMINATION OF COLLECTIVE BARGAINING AND ITS ROLE IN LABOUR RELATIONS IN NIGERIA
ABSTRACT
Just as it is common for conflicts to arise in every human relationship, the relationship between an employer and an employee is...
INFLUENCE OF SCHOOL SUPERVISION ON THE IMPLEMENTATION OF COMMERCE CURRICULUM IN SENIOR SECONDARY SCHOOLS IN NIGER STATE, NIGERIA
ABSTRACT
This study investigated the influence of school supervision on the implementation of commerce curriculum in Senior Secondary Sch...
ASSESSING THE BENEFITS OF EARLY CHILDHOOD EDUCATION IN REFUGEE CAMPS
ABSTRACT: This study Assessed the Benefits of Early Childhood Education in Refugee Camps. The objectives of this...
THE IMPACT OF SELECTED MACRO-ECONOMIC VARIABLES ON THE PROFIT PERFORMANCE OF MANUFACTURING COMPANIES IN NIGERIA
BACKGROUND OF THE STUDY
The association between macroeconomic factors and organiza ional performance ha...
THE EFFECTIVENESS OF INDUSTRY SIMULATIONS IN VOCATIONAL TRAINING
Abstract: Industry simulations are increasingly employed to bridge the gap between classroo...
