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dc.contributor.authorMohamed, Eslam
dc.date.accessioned2016-08-22T19:40:40Z
dc.date.available2016-08-22T19:40:40Z
dc.date.issued2016en
dc.identifier.urihttp://hdl.handle.net/10675.2/618646
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus. Record is embargoed until 08/01/2018en
dc.description.abstractThe stimulator of interferon genes (STING) is an adaptor protein downstream of an array of cytosolic DNA sensors such as cyclic GMP-AMP synthase (cGAS). STING activation by the second messengers, cyclic dinucleotides (CDNs) induces interferon type I (IFN-I). STING/IFN-I signaling incites autoimmunity in mice lacking the DNA catabolizing enzyme Trex-1. Paradoxically, we find the DNA sensing to activate STING/IFN-I signaling induces dendritic cells (DCs) to express indoleamine 2,3 dioxygenase (IDO), which activates regulatory T cells (Tregs). Thus treatment with DNA nanoparticles (DNPs) or CDNs to activate STING attenuated experimental autoimmune encephalomyelitis (EAE) and therapeutic responses were dependent on STING/IFN-I signaling to induce IDO. DNP and CDNs treatments were also effective in slowing type I diabetes (T1D) progression in susceptible female non-obese diabetic (NOD) mice. Recent reports revealed that DNA sensing to activate STING in DCs that engulfed dying tumor cells impeded growth of immunogenic tumors and potentiated responses to therapy. Consistent with these findings synthetic STING agonists enhanced tumor regression. Paradoxically, lewis lung carcinoma (LLC), grew slower in STING-deficient mice, revealing that STING is required for optimal LLC growth. Mechanistically, STING ablation abolished IDO upregulation in DCs located in tumor draining lymph nodes during LLC growth. Consequently, expression of the regulatory cytokine IL-10 and infiltration of myeloid derived suppressor cells (MDSCs) into the tumor microenvironment (TME) were diminished in mice lacking STING. In contrast, STING was not required for optimal growth of LLC tumors expressing neo-antigens, revealing a pivotal role for tumor antigenicity in influencing responses to DNA in the TME. Thus, DNA from dying cells are sensed in the TME to activate STING, which induces dominant regulatory responses via IDO when tumor antigenicity is low and dominant immunogenic responses when tumor antigenicity is enhanced. Collectively, these findings support the hypothesis that DNP cargo DNA and DNA from dying tumor cells is sensed to activate STING\IFN-I in regulatory DCs that suppresses T cell immunity and autoimmunity at sites of chronic inflammation associated with autoimmunity and tumor growth.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectSTINGen
dc.subjectSuppressionen
dc.subjectLLCen
dc.subjectAntigenicityen
dc.titleDNA sensing via STING regulates immunityen
dc.typeDissertationen
dc.contributor.departmentDepartment of Neuroscience and Regenerative Medicineen
dc.description.degreeDoctor of Philosophy with a Major in Molecular Medicineen
html.description.abstractThe stimulator of interferon genes (STING) is an adaptor protein downstream of an array of cytosolic DNA sensors such as cyclic GMP-AMP synthase (cGAS). STING activation by the second messengers, cyclic dinucleotides (CDNs) induces interferon type I (IFN-I). STING/IFN-I signaling incites autoimmunity in mice lacking the DNA catabolizing enzyme Trex-1. Paradoxically, we find the DNA sensing to activate STING/IFN-I signaling induces dendritic cells (DCs) to express indoleamine 2,3 dioxygenase (IDO), which activates regulatory T cells (Tregs). Thus treatment with DNA nanoparticles (DNPs) or CDNs to activate STING attenuated experimental autoimmune encephalomyelitis (EAE) and therapeutic responses were dependent on STING/IFN-I signaling to induce IDO. DNP and CDNs treatments were also effective in slowing type I diabetes (T1D) progression in susceptible female non-obese diabetic (NOD) mice. Recent reports revealed that DNA sensing to activate STING in DCs that engulfed dying tumor cells impeded growth of immunogenic tumors and potentiated responses to therapy. Consistent with these findings synthetic STING agonists enhanced tumor regression. Paradoxically, lewis lung carcinoma (LLC), grew slower in STING-deficient mice, revealing that STING is required for optimal LLC growth. Mechanistically, STING ablation abolished IDO upregulation in DCs located in tumor draining lymph nodes during LLC growth. Consequently, expression of the regulatory cytokine IL-10 and infiltration of myeloid derived suppressor cells (MDSCs) into the tumor microenvironment (TME) were diminished in mice lacking STING. In contrast, STING was not required for optimal growth of LLC tumors expressing neo-antigens, revealing a pivotal role for tumor antigenicity in influencing responses to DNA in the TME. Thus, DNA from dying cells are sensed in the TME to activate STING, which induces dominant regulatory responses via IDO when tumor antigenicity is low and dominant immunogenic responses when tumor antigenicity is enhanced. Collectively, these findings support the hypothesis that DNP cargo DNA and DNA from dying tumor cells is sensed to activate STING\IFN-I in regulatory DCs that suppresses T cell immunity and autoimmunity at sites of chronic inflammation associated with autoimmunity and tumor growth.


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