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 5000
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
An appraisal of customer trust-building measures in Islamic banking
Background of the Study
Customer trust is a cornerstone of any successful financial institution, and in Islamic banking, t...
An examination of the impact of terrorism on business investments in Birnin Kebbi Local Government Area, Kebbi State.
Chapter One: Introduction
1.1 Background of the Study
Terrorism has become a significant threat...
Analysis of AI-Based Algorithms for Detecting University Certificate Forgery in Nasarawa State University, Keffi, Nasarawa State
Background of the Study
The increasing sophistication of document forgery, particularly in academic certificates, has rais...
An investigation into substance abuse and mental health among adolescents in Delta State
Background of the Study
Substance abuse among adolescents has emerged as a major public health challenge, with far-reaching consequences...
CULTURE AND DISCRIMINATION AGAINST WOMEN IN BUCHI EMECHETA’S THE JOYS OF MOTHERHOOD AND CHIMAMANDA ADICHIE’S PURPLE HIBISCUS.
ABSTRACT &...
An investigation of maintenance charge policy impacts on operational efficiency in banking: a case study of Stanbic IBTC Bank Nigeria
Background of the Study
Maintenance charges represent an important aspect of operational revenue and cost structure in banking. Stanbic I...
THE IMPACT OF MANPOWER TRAINING AND DEVELOPMENT AS A TOOL FOR ORGANIZATIONAL PRODUCTIVITY
ABSTRACT
This study was carried out on the impact of manpower training and development as a tool for organizationa...
The Role of Collateral Requirements on SME Funding Challenges in Nigeria: A Study of SMEs in Bauchi State
Background of the Study
Collateral requirements are a major determinant of SME funding accessibility in Nigeria. Financial...
THE ROLE OF ACCOUNTING FOR DISASTER RECOVERY AND EMERGENCY FUNDS
THE ROLE OF ACCOUNTING FOR DISASTER RECOVERY AND EMERGENCY FUNDS
Abstract
This research investigates the role of accounting in...
An Evaluation of Electoral Law Enforcement in Northern Nigeria: A Case Study of Sokoto LGA, Sokoto State
Chapter One: Introduction
1.1 Background of the Study
Electoral law enforcement is crucial for e...
