Induction and Role of Indoleamine 2,3 Dioxygenase (IDO) in Controlling Responses to Influenza Infection and DNA

Hdl Handle:
http://hdl.handle.net/10675.2/325539
Title:
Induction and Role of Indoleamine 2,3 Dioxygenase (IDO) in Controlling Responses to Influenza Infection and DNA
Authors:
Li, Lingqian
Abstract:
Infections and other stimuli that disturb tissue homeostasis trigger local inflammation that activates innate and adaptive immune cells. However, activated immune cells may incite effector or regulatory responses in particular inflammatory settings. We evaluate how induced indoleamine 2, 3 dioxygenase (IDO) activity modifies immune responses in influenza infected lungs and draining lymph nodes, and in spleens following systemic treatments of DNA nanoparticles (DNPs) that trigger DNA sensors. Rapid interferon (IFN) production is a common feature of responses to both influenza and double strand DNA, and type I (IFN) and type II (IFN) IFNs are potent IDO inducers. Influenza A virus infection induced IDO activity in nonhematopoietic cells in the lungs and hematopoietic cells in mediastinal lymph nodes (msLNs). IDO induction depended on type IFN signaling in the lungs while either type I or II IFN maintained IDO activity in the msLNs. Neutrophil influx into lung bronchoalveolar lavage (BAL) and CD8+ T cell clonal expansion were attenuated by IDO expression during primary infection. IDO ablation led to a significant alteration in the repertoire of T cell receptor (TCR) V8.3 chain usage by influenza-specific memory CD8+ T cells. Thus, IDO restrained innate immune and adaptive T cell responses during primary infection and influenced memory CD8+ T cell generation. DNA introduced systemically into mice as DNPs stimulated rapid increase in IDO activity in lymphoid and mucosal tissues. DNPs triggered specific subsets of dendritic cells (DCs) expressing the B cell marker CD19 (CD19+ DCs) to upregulate IDO and acquire potent regulatory phenotypes via an IDO-dependent mechanism. DNPs were sensed by the STimulator of INterferon Genes (STING), which triggered selective expression of type I IFN by myeloid (CD11b+) DCs in spleen. In contrast, DNP induced pro-interleukin-1 (IL1was produced primarily by myeloid CD11b+ non-DCs via a STING-independent pathway. Cyclic diguanylate monophosphate (c-diGMP), a direct activator of STING also induced IDO. These findings highlight the importance of contextual tissue factors and reagent delivery routes in determining immune outcomes. Targeting this distinctive tolerogenic pathway using DNPs or c-diGMP suggests effective strategies to suppress autoimmunity and to inhibit transplant rejection.
Affiliation:
Department of Biochemistry and Molecular Biology
Issue Date:
Feb-2014
URI:
http://hdl.handle.net/10675.2/325539
Additional Links:
http://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/1518747399?accountid=12365
Type:
Dissertation
Language:
en
Appears in Collections:
Department of Biochemistry and Molecular Biology Theses and Dissertations; Theses and Dissertations

Full metadata record

DC FieldValue Language
dc.contributor.authorLi, Lingqianen
dc.date.accessioned2014-08-28T23:51:28Z-
dc.date.available2014-08-28T23:51:28Z-
dc.date.issued2014-02-
dc.identifier.urihttp://hdl.handle.net/10675.2/325539-
dc.description.abstractInfections and other stimuli that disturb tissue homeostasis trigger local inflammation that activates innate and adaptive immune cells. However, activated immune cells may incite effector or regulatory responses in particular inflammatory settings. We evaluate how induced indoleamine 2, 3 dioxygenase (IDO) activity modifies immune responses in influenza infected lungs and draining lymph nodes, and in spleens following systemic treatments of DNA nanoparticles (DNPs) that trigger DNA sensors. Rapid interferon (IFN) production is a common feature of responses to both influenza and double strand DNA, and type I (IFN) and type II (IFN) IFNs are potent IDO inducers. Influenza A virus infection induced IDO activity in nonhematopoietic cells in the lungs and hematopoietic cells in mediastinal lymph nodes (msLNs). IDO induction depended on type IFN signaling in the lungs while either type I or II IFN maintained IDO activity in the msLNs. Neutrophil influx into lung bronchoalveolar lavage (BAL) and CD8+ T cell clonal expansion were attenuated by IDO expression during primary infection. IDO ablation led to a significant alteration in the repertoire of T cell receptor (TCR) V8.3 chain usage by influenza-specific memory CD8+ T cells. Thus, IDO restrained innate immune and adaptive T cell responses during primary infection and influenced memory CD8+ T cell generation. DNA introduced systemically into mice as DNPs stimulated rapid increase in IDO activity in lymphoid and mucosal tissues. DNPs triggered specific subsets of dendritic cells (DCs) expressing the B cell marker CD19 (CD19+ DCs) to upregulate IDO and acquire potent regulatory phenotypes via an IDO-dependent mechanism. DNPs were sensed by the STimulator of INterferon Genes (STING), which triggered selective expression of type I IFN by myeloid (CD11b+) DCs in spleen. In contrast, DNP induced pro-interleukin-1 (IL1was produced primarily by myeloid CD11b+ non-DCs via a STING-independent pathway. Cyclic diguanylate monophosphate (c-diGMP), a direct activator of STING also induced IDO. These findings highlight the importance of contextual tissue factors and reagent delivery routes in determining immune outcomes. Targeting this distinctive tolerogenic pathway using DNPs or c-diGMP suggests effective strategies to suppress autoimmunity and to inhibit transplant rejection.en
dc.language.isoenen
dc.relation.urlhttp://ezproxy.augusta.edu/login?url=http://search.proquest.com/docview/1518747399?accountid=12365en
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.-
dc.subjectindoleamine 2,3 dioxygenaseen
dc.subjectinfluenza A virusen
dc.subjectDNA nanoparticleen
dc.subjectimmune suppressionen
dc.subjectStimulator of Interferon Genesen
dc.subjectdendritic cellen
dc.subjectRegulatory T Cellsen
dc.subjectType I/II interferonen
dc.subjectCyclic diguanylate monophosphateen
dc.subjectinterleukin-1 Ben
dc.titleInduction and Role of Indoleamine 2,3 Dioxygenase (IDO) in Controlling Responses to Influenza Infection and DNAen
dc.typeDissertationen
dc.contributor.departmentDepartment of Biochemistry and Molecular Biologyen
dc.description.advisorMellor, Andrewen
dc.description.committeeThompson, Stuart; He, Yukai; McGaha, Tracy; Huang, Lei; Chimoda, Michikoen
dc.description.degreeDoctor of Philosophy with a Major in Molecular Medicineen
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