Evaluation of the role of IF1 on CD4+ T cell differentiation: possible regulatory action of P2X7 and CD39

• Grant number: 22/14529-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: April 01, 2023
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Maria Regina D'Império Lima
• Grantee: Danilo Chaves da Silva Ramos de Souza
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/20432-8 - Intervention in signaling pathways associated with the recognition of cellular damage to reduce the pathology of severe forms of malaria and tuberculosis, AP.TEM

Abstract

CD4+ T cell activity is essential for the development of effective immune responses in various pathological contexts, including infection with parasites of the genus Plasmodium. In secondary lymphoid organs, CD4+ T cells differentiate into two distinct effector lineages: TFH and non-TFH cells. TFH cells proceed to germinal centers where they interact with B cells and assist them in antibody generation, whereas non-TFH cells migrate to the periphery and differentiate into specialized cytokine secretion profiles. Among the factors that influence CD4+ T-cell commitment in TFH and non-TFH lineages, it is suggested that metabolism may be determinant since TFH and non-TFH cells obtain energy by different pathways: oxidative phosphorylation and aerobic glycolysis, respectively. ATPase inhibitory factor 1 (IF1) acts as an endogenous inhibitor of mitochondrial ATP synthase. In cancer cells, the activity of IF1 promotes inhibition of oxidative phosphorylation and induction of aerobic glycolysis; in CD4+ T cells, the role of IF1 is not elucidated. Furthermore, it is possible that this process is influenced by the stimulation of extracellular ATP receptor P2X7. In experimental malaria, the absence of functional P2X7 favors the differentiation of TFH cells and impairs the differentiation of non-TFH cells, which can be reversed by pharmacological inhibition of ATP synthase. P2X7 stimulation is controlled by the ectonucleotidase CD39; its role in CD4+ T cell differentiation is not fully elucidated. The aim of this study is to evaluate the role of IF1 in CD4+ T cell differentiation, as well as the influence of P2X7 and CD39 in this process. The in vivo analysis will be performed in an experimental malaria model given the relevance of this infectious disease for human health and the large availability of data regarding TH1/TFH differentiation obtained in mice with parasite-specific transgenic T cells. The studies will be validated in cells differentiated in vitro under TH1 polarizing conditions.