Study of the role of CD39 ectonucleotidase and adenosine production in the differentiation and function of Tfr cells

• Grant number: 22/07035-3
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): December 01, 2022
• Effective date (End): July 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Paulo Henrique Lisboa Raeder
• Supervisor: Peter Sage
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Harvard University, Boston, United States
• Associated to the scholarship: 20/01197-6 - Role of P2X7 receptor and CD39 ectonucleotidase in follicular regulatory T lymphocytes during experimental Malaria, BP.DD

Abstract

The germinal center reaction develops in secondary lymphoid organs and is essential for the production of high-affinity antibodies. These antibodies can contribute to vaccine response and elimination of pathogens but can lead to the emergence of autoimmune diseases mediated by autoantibodies. Thus, the germinal center must be finely regulated to prevent harmful responses. Tfr cells are able to suppress autoantibody production and optimize the humoral immune response against foreign antigens (pathogens and vaccines). The regulatory mechanisms used by Tfr cells remain an important field to be investigated. We hypothesize that adenosine production from extracellular ATP by CD39 and CD73 ectonucleotidases expressed by Tfr cells constitutes an important regulatório mechanism used by Tfr cells to prevent autoantibody production. We will perform in vitro and in vivo assays to evaluate the role of CD39 and adenosine production in Tfr differentiation and function. Besides that, we will use mice in which we can delete the TFR cell population, CD39 and adenosine receptor-deficient mice, transcriptomic analysis, and confocal microscopy to elucidate the importance of CD39 to the regulatory function of Tfr cells and to control the extracellular ATP/adenosine balance in germinal center reaction. This analysis will bring important gains to the current knowledge about the differentiation and function of Tfr cells and purinergic signaling in the germinal center. (AU)