To Affinity and Beyond: T cell receptor strength and its role in T cell development and function 公开
Martinez, Ryan (Spring 2018)
Abstract
Functionality of the adaptive immune system depends on its ability to distinguish self and foreign antigens. However there is a balancing act the adaptive system must make, as it needs to recognize a wide range of diverse epitopes, but also distinguish between epitopes with astonishing specificity. The diversity of the adaptive immune system originates from the semi-random rearrangement of multiple gene segments to form a unique lymphocyte receptor. Mechanisms during lymphocyte development remove cells whose receptor either cannot recognize self-antigen or recognize self-antigen too well. Traditionally, this process removes cells that will not contribute to the immune response and those cells most likely to cause autoimmunity, respectively. The remaining lymphocytes then enter the periphery to protect the host from foreign pathogens. This education on self-antigen during development is intriguing, as lymphocytes must be made to recognize all potential antigens during an infection, even though they have never seen the antigens previously. Once the naïve lymphocytes have encountered antigen, many factors contribute to the fate of these cells, but the biophysical characteristics of the lymphocyte receptor interacting with peptide presented by major histocompatibility complex (pMHC) directs the initial signaling events and controls lymphocyte functionality. This receptor:ligand interaction is fundamentally important as it controls many aspects of the development and intrinsic functions of the lymphocyte. In this introduction I will discuss how central tolerance discriminates between self vs non-self as well as how these mechanisms alter the functionality and detection of lymphocytes throughout the immune response.
Table of Contents
Table of Contents
Introduction ……………………...……………………………………………………1-21
Chapter 1: Targeted loss of SHP1 in murine thymocytes dampens TCR signaling late in selection ……………………………………………………………………………...22-46
Figure 1……………………………………………………………………….37-38
Figure2………………………………………………………………….…….39-40
Figure 3…………………………………………………………………….....41-42
Figure 4………...……………………………………………………………..43-44
Figure 5……………………………………………………………………….45-46
Chapter 2: Dual positive selection mechanisms limit autoimmune demyelinating disease
………………………………………………………………………………..47-83
Figure 1…………………………………………………………………….....67-68
Figure 2……………………………………………………………………….69-70
Figure 3…………………………………………………………………….....71-72
Figure 4…………………………………………………………………...…..73-74
Figure 5…………………………………………………………………….....75-76
Figure 6…………………………………………………………………...…..77-78
Figure 7…………………………………………………………………...…..79-80
Figure 8………………………………………………………………….……81-82
Supplemental Figure 1………………………………………………….……..…83
Chapter 3: Large numbers of lower-affinity CD4 T cells enter and participate in the primary immune response…………………………………………………………..84-117
Figure 1…………………………………….………………………….…….107-08
Figure 2………………………………………………………………...……109-10
Figure 3……………………………………………………………….……..111-12
Figure 4………………………………………………………………...……113-14
Figure 5……………………………………………………………….……..115-16
Supplemental Figures………………………………………………………..….117
Discussion………………………………………………………..……………….. 118-129
References……………………………………………………………..…………..130-166
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