title: Limitations of Foxp3(+) Treg depletion following viral infection in DEREG mice.
abstract: Regulatory T cells (Tregs) play a critical role in maintaining tissue homeostasis and preventing the development of immunopathology. Depletion of REGulatory T cell (DEREG) mice express a diphtheria toxin receptor (DTR)-eGFP transgene under the control of the Foxp3 promoter allowing for Treg depletion following diphtheria toxin (DT) administration. DEREG mice have been utilized to investigate the role of Tregs in a wide range of disease settings. Administration of DT to naïve DEREG mice resulted in the rapid depletion of Foxp3(+) Tregs from the peripheral blood. However, by day 4 post-DT administration, a GFP(-) Foxp3(+) Treg population emerged that lacked expression of the DTR transgene and was resistant to further depletion by additional DT treatment. We further evaluated the impact of Treg depletion during both acute and chronic viral infections. Similar to naïve mice, Treg numbers rapidly rebounded during an inflammatory setting following an acute viral infection. DT treatment of both wild-type (WT) and DEREG mice following both acute and chronic viral infections induced exacerbated disease as compared to PBS-treated controls. Furthermore, following a chronic systemic viral infection, DT treatment resulted in nearly 100% mortality in both WT and DEREG mice while the PBS-treated controls survived. Our results demonstrate that Treg depletion in DEREG mice is transient and that DT administration can have adverse effects during virus-induced inflammation and highlights the critical need to include DT-treated WT mice when using DTR models to control for DT-mediated toxicity.
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Allison F
authors.initials: AF
authors.lastname: Christiaansen
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Paola M
authors.initials: PM
authors.lastname: Boggiatto
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, USA; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA. Electronic address: steven-varga@uiowa.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Varga
mesh_terms: D000818:Animals; D004167:Diphtheria Toxin / Q000008:administration & dosage; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D007249:Inflammation / Q000276:immunology / Q000821:virology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019076:Transgenes / Q000235:genetics
chemical_list: D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D049452:Green Fluorescent Proteins
keywords: Lung; Regulatory T cell; Spleen; T cell; Viral