title: Immunoendocrine dysbalance during uncontrolled T. cruzi infection is associated with the acquisition of a Th-1-like phenotype by Foxp3(+) T cells.
abstract: We previously showed that Trypanosomacruzi infection in C57BL/6 mice results in a lethal infection linked to unbalanced pro- and anti-inflammatory mediators production. Here, we examined the dynamics of CD4(+)Foxp3(+) regulatory T (Treg) cells within this inflammatory and highly Th1-polarized environment. Treg cells showed a reduced proliferation rate and their frequency is progressively reduced along infection compared to effector T (Teff) cells. Also, a higher fraction of Treg cells showed a naïve phenotype, meanwhile Teff cells were mostly of the effector memory type. T. cruzi infection was associated with the production of pro- and anti-inflammatory cytokines, notably IL-27p28, and with the induction of T-bet and IFN-γ expression in Treg cells. Furthermore, endogenous glucocorticoids released in response to T. cruzi-driven immune activation were crucial to sustain the Treg/Teff cell balance. Notably, IL-2 plus dexamethasone combined treatment before infection was associated with increased Treg cell proliferation and expression of GATA-3, IL-4 and IL-10, and increased mice survival time. Overall, our results indicate that therapies aimed at specifically boosting Treg cells, which during T. cruzi infection are overwhelmed by the effector immune response, represent new opportunities for the treatment of Chagas disease, which is actually only based on parasite-targeted chemotherapy.
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina.
authors.forename: Florencia B
authors.initials: FB
authors.lastname: González
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina.
authors.forename: Silvina R
authors.initials: SR
authors.lastname: Villar
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernández Bussy
authors.affiliation: INSERM U955, Equipe 21, Créteil, France.
authors.forename: Gaëlle H
authors.initials: GH
authors.lastname: Martin
authors.affiliation: INSERM U932, 26 rue d'Ulm, 75005 Paris, France; Institut Curie, Section Recherche, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Pérol
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina.
authors.forename: Romina
authors.initials: R
authors.lastname: Manarin
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina.
authors.forename: Silvana V
authors.initials: SV
authors.lastname: Spinelli
authors.affiliation: Université Paris-Est, UMR_S955, UPEC, Créteil, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pilon
authors.affiliation: INSERM U955, Equipe 21, Créteil, France; Université Paris-Est, UMR_S955, UPEC, Créteil, France; AP-HP, Hôpital Henri-Mondor - A. Chenevier, CIC-BT-504, Créteil, France.
authors.forename: José Laurent
authors.initials: JL
authors.lastname: Cohen
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Bottasso
authors.affiliation: INSERM U932, 26 rue d'Ulm, 75005 Paris, France; Institut Curie, Section Recherche, 26 rue d'Ulm, 75005 Paris, France; INSERM Center of Clinical Investigation (CBT507 IGR-Curie), 75005 Paris, France. Electronic address: eliane.piaggio@curie.fr.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
authors.affiliation: IDICER-CONICET, Institute of Clinical and Experimental Immunology of Rosario and Immunology Institute, Faculty of Medical Sciences, National University of Rosario, Argentina. Electronic address: perez_anarosa@yahoo.com.ar.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Pérez
mesh_terms: D000315:Adrenalectomy; D000818:Animals; D002598:Chagas Cardiomyopathy / Q000276:immunology / Q000473:pathology; D014355:Chagas Disease / Q000276:immunology* / Q000473:pathology; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000494:pharmacology; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D014349:Trypanosoma cruzi / Q000276:immunology*
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D005938:Glucocorticoids; C556062:IL10 protein, mouse; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D003907:Dexamethasone; D007371:Interferon-gamma; D003345:Corticosterone
keywords: Chagas disease; Glucocorticoids; IFN-γ; IL-2; Regulatory T cells