title: Blimp-1-Dependent IL-10 Production by Tr1 Cells Regulates TNF-Mediated Tissue Pathology.
abstract: Tumor necrosis factor (TNF) is critical for controlling many intracellular infections, but can also contribute to inflammation. It can promote the destruction of important cell populations and trigger dramatic tissue remodeling following establishment of chronic disease. Therefore, a better understanding of TNF regulation is needed to allow pathogen control without causing or exacerbating disease. IL-10 is an important regulatory cytokine with broad activities, including the suppression of inflammation. IL-10 is produced by different immune cells; however, its regulation and function appears to be cell-specific and context-dependent. Recently, IL-10 produced by Th1 (Tr1) cells was shown to protect host tissues from inflammation induced following infection. Here, we identify a novel pathway of TNF regulation by IL-10 from Tr1 cells during parasitic infection. We report elevated Blimp-1 mRNA levels in CD4+ T cells from visceral leishmaniasis (VL) patients, and demonstrate IL-12 was essential for Blimp-1 expression and Tr1 cell development in experimental VL. Critically, we show Blimp-1-dependent IL-10 production by Tr1 cells prevents tissue damage caused by IFNγ-dependent TNF production. Therefore, we identify Blimp-1-dependent IL-10 produced by Tr1 cells as a key regulator of TNF-mediated pathology and identify Tr1 cells as potential therapeutic tools to control inflammation.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|University of Queensland, School of Medicine, Brisbane, Australia.
authors.forename: Marcela
authors.initials: M
authors.lastname: Montes de Oca
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Netaji Subhas Institute of Technology, New Delhi, India.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Fabian
authors.initials: F
authors.lastname: de Labastida Rivera
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Meru
authors.initials: M
authors.lastname: Sheel
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Queensland University of Technology, Institute of Health and Biomedical Innovation, Brisbane, Australia.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Faleiro
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Griffith University, Institute of Glycomics, Gold Coast, Australia.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Bunn
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Lynette
authors.initials: L
authors.lastname: Beattie
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|Griffith University, School of Natural Sciences, Nathan, Australia.
authors.forename: Susanna S
authors.initials: SS
authors.lastname: Ng
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.|University of Queensland, School of Medicine, Brisbane, Australia.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Edwards
authors.affiliation: University of Manchester, Faculty of Life Sciences, Manchester, United Kingdom.
authors.forename: Werner
authors.initials: W
authors.lastname: Muller
authors.affiliation: Walter and Eliza Hall Medical Research Institute, Division of Molecular Immunology, Melbourne, Australia.|The University of Melbourne, Department of Medical Biology, Melbourne, Australia.
authors.forename: Erika
authors.initials: E
authors.lastname: Cretney
authors.affiliation: Walter and Eliza Hall Medical Research Institute, Division of Molecular Immunology, Melbourne, Australia.|The University of Melbourne, Department of Medical Biology, Melbourne, Australia.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Banaras Hindu University, Institute of Medical Sciences, Varanasi, Uttar Pradesh, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Walter and Eliza Hall Medical Research Institute, Division of Molecular Immunology, Melbourne, Australia.|The University of Melbourne, Department of Medical Biology, Melbourne, Australia.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000473:pathology; D008288:Malaria / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1