Loss- and Gain-of-Function Approaches Indicate a Dual Role Exerted by Regulatory T Cells in Pulmonary Paracoccidioidomycosis

Author(s)

Bazan, Silvia B. ^[1] ; Costa, Tania A. ^[1] ; de Araujo, Eliseu Frank ^[1] ; Feriotti, Claudia ^[1] ; Loures, Flavio V. ^[1] ; Pretel, Fernando D. ^[2] ; Calich, Vera L. G. ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, BR-05508 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Ctr Facil Apoio Pesquisa CEFAP, BR-05508 Sao Paulo - Brazil

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 9, n. 10 OCT 2015.
• Web of Science Citations: 4

Abstract

Paracoccidioidomycosis (PCM), is a pulmonary fungal disease whose severity depends on the adequate development of T cell immunity. Although regulatory T (Treg) cells were shown to control immunity against PCM, deleterious or protective effects were described in different experimental settings. To clarify the function of Treg cells in pulmonary PCM, loss and gain-of-function approaches were performed with Foxp3GFP knock-in mice and immunodeficient Rag1(-/-)mice, respectively, which were intratracheally infected with 10(6) yeast cells. The activity of Foxp3-expressing Treg cells in pulmonary PCM was determined in Foxp3GFP transgenic mice. First, it was verified that natural Treg cells migrate to the lungs of infected mice, where they become activated. Depletion of Treg cells led to reduced fungal load, diminished pathogen dissemination and increased Th1/Th2/Th17 immunity. Further, adoptive transfer of diverse T cell subsets to Rag1(-/-)mice subsequently infected by the pulmonary route demonstrated that isolated CD4(+) Foxp3(+) Treg cells were able to confer some degree of immunoprotection and that CD4(+) Foxp3-T cells alone reduced fungal growth and enhanced T cell immunity, but induced vigorous inflammatory reactions in the lungs. Nevertheless, transfer of Treg cells combined with CD4(+) Foxp3-T cells generated more efficient and balanced immune Th1/Th2/Th17 responses able to limit pathogen growth and excessive tissue inflammation, leading to regressive disease and increased survival rates. Altogether, these loss-and gain-of-function approaches allow us to clearly demonstrate the dual role of Treg cells in pulmonary PCM, their deleterious effects by impairing T cell immunity and pathogen eradication, and their protective role by suppressing exacerbated tissue inflammation. (AU)

• FAPESP's process: 12/01765-8 - CHARACTERIZATION OF REGULATORY T CELLS IN LUNG PARACOCCIDIOIDOMYCOSIS (PCM) USING C57BL/6 MICE TRANSGENIC FOR FOXP3-GFP EXPRESSION
• Grantee: Silvia Boschi Bazan
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 11/51258-2 - Influence of the enzyme indoleamine-2,3-dioxygenase (IDO) in the differentiation and function of dendritic cells and regulatory T cells in the pulmonary paracoccidioidomycosis of resistant and susceptible mice to P. brasiliensis infection
• Grantee: Vera Lucia Garcia Calich
• Support Opportunities: Regular Research Grants