T Cell Priming Through Serial Encounters Lowers the Probability of Autoimmunity against DC-self Open Access

Abstract

During T cell development, T cells are clonally deleted by negative selection in the thymus in order to provide tolerance against self-reactive lymphocytes. The large number of possible self-peptide MHCs (spMHCs) and the relatively short period for negative selection in the thymus impose a quantitative constraint on the efficiency of clonal deletion against self-reactive lymphocytes. It is, however, particularly important to delete T cells specific for dendritic cell endogenous sp-MHCs – this is because DCs play a central role in the activation of T cells and the generation of immune responses. Since DCs in the thymus have very similar patterns of gene expression as DCs in the periphery, Matzinger has hypothesized that it may be possible to reliably delete all T cells specific for DC-endogenous sp-MHC (DC-self). Here we use quantitative models to explore Matzingers hypothesis. We begin with a simple model where the rules for stimulation of a T cell in the thymus is the same as that in the periphery. In this scenario, we find that it may be difficult to reliably delete T cells specific for rare DC-self. We then explore how differences in the dynamics of T cell activation in the thymus vs. the periphery may allow us to reliably avoid stimulation of T cells against DC-self. Our results suggest that the complex pattern of T cell priming in secondary lymphoid organs may arise, at least in part, to prevent the stimulation of autoimmune T cells responses to DC-self. 

Table of Contents

Introduction

1 1.1 CentralToleranceandItsLimitations...................... 2

1.2 PeripheralToleranceMechanisms ........................ 3

1.3 Tcellactivationrequirements .......................... 4

1.4 OurFocus..................................... 6

Model 1- Single-hit model 7

2.1 Model construction ................................ 8

2.2 Model results ................................... 9

2.2.1 Changingn2................................ 11

2.2.2 ChangingFactork ............................ 11

Model 2- Serial Encounter Model 15

3.1 Model construction ................................ 15

3.2 Modelresults ................................... 18

Model 3- Serial Encounter Model with decay / decay model 22

4.1 Modelconstruction ................................ 22

4.2 Modelresults ................................... 25

Discussion 31

5.1 OurModels .................................... 31

5.2 EfficiencyofTheSystem............................. 32

5.3 BiochemicalRelevance .............................. 35

5.4 PeripherialToleranceMechanisms........................ 37

5.5 BeyondDC-self .................................. 38

Appendix

Mu ̈ller & Bonhoeffer 39

Chan et al., 42

Affect of changing n2 and k in model 1 45

Q & A 47

Bibliography 51 

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, General Biology, Cell Biology, Molecular
Keyword	Immune Tolerance Modeling Immunology T cell development
Committee Chair / Thesis Advisor	Rustom Antia, Emory University
Committee Members	Sarah Fankhauser, Emory University Byron Au-Yeung, Emory University

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