Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group


First Advisor

Edward M. Behrens


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.


Available to all on Monday, April 10, 2023

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