title: Activated CD8+ T cells induce expansion of Vβ5+ regulatory T cells via TNFR2 signaling.
abstract: Vβ5(+) regulatory T cells (Tregs), which are specific for a mouse endogenous retroviral superantigen, become activated and proliferate in response to Friend virus (FV) infection. We previously reported that FV-induced expansion of this Treg subset was dependent on CD8(+) T cells and TNF-α, but independent of IL-2. We now show that the inflammatory milieu associated with FV infection is not necessary for induction of Vβ5(+) Treg expansion. Rather, it is the presence of activated CD8(+) T cells that is critical for their expansion. The data indicate that the mechanism involves signaling between the membrane-bound form of TNF-α on activated CD8(+) T cells and TNFR2 on Tregs. CD8(+) T cells expressing membrane-bound TNF-α but no soluble TNF-α remained competent to induce strong Vβ5(+) Treg expansion in vivo. In addition, Vβ5(+) Tregs expressing only TNFR2 but no TNFR1 were still responsive to expansion. Finally, treatment of naive mice with soluble TNF-α did not induce Vβ5(+) Treg expansion, but treatment with a TNFR2-specific agonist did. These results reveal a new mechanism of intercellular communication between activated CD8(+) T cell effectors and Tregs that results in the activation and expansion of a Treg subset that subsequently suppresses CD8(+) T cell functions.
authors.affiliation: Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany;
authors.forename: Jara J
authors.initials: JJ
authors.lastname: Joedicke
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Lara
authors.initials: L
authors.lastname: Myers
authors.affiliation: Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Carmody
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840;
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Messer
authors.affiliation: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg 97080, Germany;
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
authors.affiliation: Institute for Immunology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany;
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.affiliation: Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany; Department of Molecular Medicine II, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany; and.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.affiliation: Department of Medical Biophysics and Immunology, The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840; khasenkrug@nih.gov ulf.dittmer@uni-due.de.
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Hasenkrug
authors.affiliation: Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany; khasenkrug@nih.gov ulf.dittmer@uni-due.de.
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics; D005260:Female; D005622:Friend murine leukemia virus / Q000276:immunology; D007942:Leukemia, Experimental / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000819:agonists / Q000276:immunology*; D012192:Retroviridae Infections / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014412:Tumor Virus Infections / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C113248:T cell receptor peptide Vbeta5.2; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; C569468:iRhom2 protein, mouse
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