Regulation Of Selection And Central Tolerance By The N-Terminal Region Of Rag1

Loading...
Thumbnail Image
Degree type
Doctor of Philosophy (PhD)
Graduate group
Immunology
Discipline
Subject
Allergy and Immunology
Immunology and Infectious Disease
Medical Immunology
Funder
Grant number
License
Copyright date
2021-08-31T20:20:00-07:00
Distributor
Related resources
Author
Burn, Thomas Niels
Contributor
Abstract

The RAG1/RAG2 complex rearranges antigen receptor gene segments during VDJ recombination to allow for the generation of a vast array of antigen receptors with specificities against a virtually infinite number of insults. Direct consequences of VDJ recombination include the formation of non-functional receptors, and receptors that are self-reactive. For  T cells, mechanisms have evolved to delete cells bearing non-functional and self-reactive T cell receptors (TCRs) from the peripheral repertoire. These mechanisms rely on self-antigen:TCR interactions of intermediate affinity during development. However, the requirement for TCR selection on self-peptides results in a tenuous state where some autoreactive TCRs might not signal for deletion. A mechanism to limit this outcome is one where T cells have heightened TCR sensitivity during development such that the self-antigen they are selected on will no longer be stimulatory upon reencounter in the periphery. How this mechanism is regulated is unknown. The RAG1/RAG2 proteins have recently been shown to have functions in addition to VDJ recombination, including induction of a transcriptional program that is necessary for the expression of a number of lymphocyte-specific genes. We show that the N-terminal domain of RAG1 acts to control expression of a number of proteins during T cell development. Identification of a novel nonsense mutation in the N-terminal region of RAG1 lead us to identify a number of N-truncated isoforms that are made via internal translation initiation. Using a mouse with an inactivating mutation in the N-terminal E3 ligase domain of RAG1, we show that N-terminal RAG1 activity is essential for the upregulation of a number of TCR signaling molecules during development. In the absence of this activity, positive and negative selection are impaired, and mature T cells are hyper-active and cause disseminated pathology when transferred into RAG1-/- hosts. Correspondingly, mutations in the N-terminal, non-catalytic region of RAG1 are associated with autoimmune diseases. We propose a model where RAG1 acts as a biological clock to tune up TCR signaling during development; and hypothesize that N-truncated RAG1 isoforms can have regulatory roles in VDJ recombination and perhaps lead to heterogenous self-antigen reactivity within developing thymocytes.

Advisor
Edward M. Behrens
Date of degree
2020-01-01
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation