TCDD and CH223191 alter T cell balance but fail to induce anti-inflammatory response in adult lupus mice

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dc.contributor.authorGutierrez, Fernandoen
dc.contributor.authorMurphy, Quiyana M.en
dc.contributor.authorSwartwout, Brianna K.en
dc.contributor.authorRead, Kaitlin A.en
dc.contributor.authorEdwards, Michael R.en
dc.contributor.authorAbdelhamid, Leilaen
dc.contributor.authorCabana-Puig, Xavieren
dc.contributor.authorTesterman, James C.en
dc.contributor.authorXu, Tianen
dc.contributor.authorLu, Ranen
dc.contributor.authorAmin, Pavlyen
dc.contributor.authorCecere, Thomas E.en
dc.contributor.authorReilly, Christopher M.en
dc.contributor.authorOestreich, Kenneth J.en
dc.contributor.authorCiupe, Stanca M.en
dc.contributor.authorLuo, Xin M.en
dc.date.accessioned2024-12-19T15:20:25Zen
dc.date.available2024-12-19T15:20:25Zen
dc.date.issued2024-02-14en
dc.description.abstractAryl hydrocarbon receptor (AhR) responds to endogenous and exogenous ligands as a cytosolic receptor, transcription factor, and E3 ubiquitin ligase. Several studies support an anti-inflammatory effect of AhR activation. However, exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during early stages of development results in an autoimmune phenotype and exacerbates lupus. The effects of TCDD on lupus in adults with pre-existing autoimmunity have not been described. We present novel evidence that AhR stimulation by TCDD alters T cell responses but fails to impact lupus-like disease using an adult mouse model. Interestingly, AhR antagonist CH223191 also changed T cell balance in our model. We next developed a conceptual framework for identifying cellular and molecular factors that contribute to physiological outcomes in lupus and created models that describe cytokine dynamics that were fed into a system of differential equations to predict the kinetics of T follicular helper (Tfh) and regulatory T (Treg) cell populations. The model predicted that Tfh cells expanded to larger values following TCDD exposure compared with vehicle and CH223191. Following the initial elevation, both Tfh and Treg cell populations continuously decayed over time. A function based on the ratio of predicted Treg/Tfh cells showed that Treg cells exceed Tfh cells in all groups, with TCDD and CH223191 showing lower Treg/Tfh cell ratios than the vehicle and that the ratio is relatively constant over time. We conclude that AhR ligands did not induce an anti-inflammatory response to attenuate autoimmunity in adult lupus mice. This study challenges the dogma that TCDD supports an immunosuppressive phenotype.en
dc.description.versionPublished versionen
dc.format.extentPages 172-181en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.4049/immunohorizons.2300023en
dc.identifier.eissn2573-7732en
dc.identifier.issn2573-7732en
dc.identifier.issue2en
dc.identifier.orcidCiupe, Mihaela [0000-0002-5386-6946]en
dc.identifier.orcidLuo, Xin [0000-0002-2809-5836]en
dc.identifier.orcidCecere, Thomas [0000-0001-9558-0615]en
dc.identifier.other266694 (PII)en
dc.identifier.pmid38353996en
dc.identifier.urihttps://hdl.handle.net/10919/123835en
dc.identifier.volume8en
dc.language.isoenen
dc.publisherThe American Association of Immunologistsen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/38353996en
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshAzo Compoundsen
dc.subject.meshPyrazolesen
dc.subject.meshAnti-Inflammatory Agentsen
dc.subject.meshT-Lymphocytes, Regulatoryen
dc.subject.meshPolychlorinated Dibenzodioxinsen
dc.titleTCDD and CH223191 alter T cell balance but fail to induce anti-inflammatory response in adult lupus miceen
dc.title.serialImmunoHorizonsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dcterms.dateAccepted2024-01-16en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Scienceen
pubs.organisational-groupVirginia Tech/Science/Mathematicsen
pubs.organisational-groupVirginia Tech/Veterinary Medicineen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/Biomedical Sciences and Pathobiologyen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Science/COS T&R Facultyen
pubs.organisational-groupVirginia Tech/Veterinary Medicine/CVM T&R Facultyen

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