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

The activity of CD4+ T cells is essential for the development of effective immune responses in several pathological contexts, including infection by parasites of the genus Plasmodium. In secondary lymphoid organs, CD4+ T cells differentiate into two distinct effector lineages: TFH cells and non-TFH cells. TFH cells travel to the germinal center where they interact with B cells and help them generate antibodies, whereas non-TFH cells migrate to the periphery and differentiate into profiles specialized in cytokine secretion. Among the factors that influence the commitment of CD4+ T cells in TFH and non-TFH cell lines, it is suggested that metabolism may be determinant since TFH and non-TFH cells obtain energy through different pathways: oxidative phosphorylation and aerobic glycolysis, respectively. The ATPase 1 inhibitory factor (IF1) acts as an endogenous inhibitor of mitochondrial ATP synthase. In cancer cells, the action of IF1 promotes the inhibition of oxidative phosphorylation and the 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 stimulation of the extracellular ATP receptor P2X7. In an experimental malaria model, the absence of functional P2X7 favors the differentiation of TFH cells and hinders the differentiation of non-TFH cells, which can be reversed through the pharmacological inhibition of ATP synthase. P2X7 stimulation is controlled by CD39 ectonucleotidase; its role in the differentiation of CD4+ T cells is not fully elucidated. The in vivo analysis will be carried out in an experimental malaria model in view of the relevance of this infectious disease to human health and the wide availability of data regarding the TH1/TFH differentiation obtained in mice with transgenic T cells specific to the parasite. The studies will be validated in cells differentiated in vitro for the TH1 pattern.

Project details

Basic Science

Apr 2023 — Feb 2025

Brazil