Regulation of adaptive immunity by extracellular ATP

Adenosine-triphosphate (ATP) is the source of chemical energy for the majority of cellular functions, serves as a substrate in signal transduction pathways and is incorporated into nucleic acids during DNA replication and transcription. In addition, eukaryotic cells release ATP, which acts as a signalling molecule in an autocrine/paracrine fashion by activating purinergic P2 receptors in the plasma membrane. This family of receptors includes non-selective cationic channels (named P2X) and G protein coupled receptors (named P2Y). In the T cell, P2X7 is the most abundantly expressed receptor subtype. Its prolonged stimulation or high concentration of ATP determine the opening of a pore permeable to molecules up to 900 Da and cell death. We aim at understanding the role of P2X7 in regulating T cell homeostasis and adaptive immunity in different physiological and pathological conditions. P2rx7 expression is robustly upregulated in T effector/memory (TEM) cells and protracted P2X7 stimulation results in cell death. Naïve T cells injected into lymphopenic hosts acquire phenotypic characteristics of memory cells and undergo extensive proliferation, referred to as homeostatic expansion. Deletion of P2rx7 confers enhanced reconstitution potential to T cells. The enhanced responsiveness of P2rx7-/- T cells can also induce autoimmune responses. Notably, patients with systemic lupus erythematosus show reduced P2X7 activity in T follicular helper cells, thereby suggesting a possible role of P2X7 in limiting immunopathological responses. We are presently addressing the mechanisms involved in P2X7 mediated control of immunopathology.

Projects

  • Signal transduction and transcriptional regulation by P2X7 receptor in T cells.
  • Role of P2X7 receptor in T follicular helper cells in limiting generation of autoantibodies and immunopathology in systemic lupus erythematosus.

Team

Nome / NameRuolo / RoleEmail
Elisa RottoliPh.D studentrottoli@ingm.org

Publications

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