Characterization of Regulatory T cells in lung paracoccidioidomycosis (PCM) Using C57BL/6 mice transgenic for FoxP3-GFP expression

• Grant number: 12/01765-8
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): June 01, 2012
• Effective date (End): May 31, 2014
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Vera Lucia Garcia Calich
• Grantee: Silvia Boschi Bazan
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Regulatory T cells (Treg) include two major subsets: natural Treg, which recognize auto-antigens, and induced Treg, CD4+CD25- T lymphocytes which, under specific stimulatory conditions, differentiate into CD4+CD25+Foxp3+ cells with suppressor activity and which can recognize foreign antigens or antigens from infectious agents. Using an isogenic murine model for PCM developed in our laboratory we have demonstrated that Treg exert a deleterious effect on both fungi-resistant (A/Sn) and -susceptible (B10.A) mice. Treg depletion led to regressive and less severe infection, besides diminished tissue pathology in both strains. Moreover, reduction of the Treg cell population implies Th17 expansion and vice-versa1,2,3,4. Nonetheless, the immunoregulatory phenomena which control PCM require deeper investigations. The main purpose of this study is to characterize the development, the location and the function of Treg cells in the lung and draining lymph nodes of C57BL/6 (B6) mice transgenic for GFP (green fluorescent protein) expression under the control of Foxp3 gene, a classical marker of Treg cells. The presence of CD4+ T cells, CD8+ T cells, F4/80+ (macrophages) and Foxp3+GFP+ cells will be initially characterized in the lungs of B6-Foxp3-GFP mice infected or not intratracheally with P. brasiliensis. Foxp3+GFP+ phenotype and behaviour will be evaluated after isolation and adoptive transfer into RAG-/-mice (T- and B-cells deficient). Different groups of animals will receive naïve T cells (CD4+CD25-), Treg cells (CD4+CD25+Foxp3+GFP+), or both cell populations, and will be infected with the fungus. Disease severity will be evaluated through characterization of fungal burden in the tissues, histopathology and Th1/Th2/Th17 immunity development. Additional studies with mice depleted of Treg cells by monoclonal anti-CD25 will complete the data about the importance of these cells in PCM.

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BAZAN, SILVIA B.; COSTA, TANIA A.; DE ARAUJO, ELISEU FRANK; FERIOTTI, CLAUDIA; LOURES, FLAVIO V.; PRETEL, FERNANDO D.; CALICH, VERA L. G. Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis. PLoS Neglected Tropical Diseases, v. 9, n. 10 OCT 2015. Web of Science Citations: 4.

FERIOTTI, CLAUDIA; BAZAN, SILVIA B.; LOURES, FLAVIO V.; ARAUJO, ELISEU F.; COSTA, TANIA A.; CALICH, VERA L. G. Expression of dectin-1 and enhanced activation of NALP3 inflammasome are associated with resistance to paracoccidioidomycosis. FRONTIERS IN MICROBIOLOGY, v. 6, SEP 3 2015. Web of Science Citations: 15.

ARAUJO, ELISEU F.; LOURES, FLAVIO V.; BAZAN, SILVIA B.; FERIOTTI, CLAUDIA; PINA, ADRIANA; SCHANOSKI, ALESSANDRA S.; COSTA, TANIA A.; CALICH, VERA L. G. Indoleamine 2,3-Dioxygenase Controls Fungal Loads and Immunity in Paracoccidioidomicosis but is More Important to Susceptible than Resistant Hosts. PLoS Neglected Tropical Diseases, v. 8, n. 11 NOV 2014. Web of Science Citations: 14.

FELONATO, MAIRA; PINA, ADRIANA; DE ARAUJO, ELISEU FRANK; LOURES, FLAVIO V.; BAZAN, SILVIA B.; FERIOTTI, CLAUDIA; CALICH, VERA L. G. Anti-CD25 Treatment Depletes Treg Cells and Decreases Disease Severity in Susceptible and Resistant Mice Infected with Paracoccidioides brasiliensis. PLoS One, v. 7, n. 11 NOV 30 2012. Web of Science Citations: 29.