{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/31196"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/31196","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"Regulation Of Selection And Central Tolerance By The N-Terminal Region Of Rag1","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Burn, Thomas Niels"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Edward M. Behrens"],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020","date_published":"2020","updated_at":"2026-07-24T03:47:06Z","subjects":[],"languages":["en"],"rights":["Thomas Niels Burn"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/31196","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Edward M. 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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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy (PhD)"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Regulation Of Selection And Central Tolerance By The N-Terminal Region Of Rag1"]}]}],"canonical_facts":{"dc:contributor.advisor":["Edward M. Behrens"],"dc:creator":["Burn, Thomas Niels"],"dc:date":["2023-05-18T01:15:36.000"],"dc:date.accessioned":["2023-05-22T18:03:00Z"],"dc:date.available":["2023-04-10T00:00:00Z"],"dc:date.issued":["2020"],"dc:description.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."],"dc:description.degree":["Doctor of Philosophy (PhD)"],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/31196"],"dc:language":["en"],"dc:rights":["Thomas Niels Burn"],"dc:title":["Regulation Of Selection And Central Tolerance By The N-Terminal Region Of Rag1"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:47:06Z"}