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.
- 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.
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|Elisa Rottoli||Ph.D firstname.lastname@example.org|
- T Follicular Helper Cells Promote a Beneficial Gut Ecosystem for Host Metabolic Homeostasis by Sensing Microbiota-Derived Extracellular ATP.
Perruzza L, Gargari G, Proietti M, Fosso B, D’Erchia AM, Faliti CE, Rezzonico-Jost T, Scribano D, Mauri L, Colombo D, Pellegrini G, Moregola A, Mooser C, Pesole G, Nicoletti M, Norata GD, Geuking MB, McCoy KD, Guglielmetti S, Grassi F.
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- Ectonucleotidase activity and immunosuppression in astrocyte-CD4 T cell bidirectional signaling.
Filipello F, Pozzi D, Proietti M, Romagnani A, Mazzitelli S, Matteoli M, Verderio C, Grassi F.
Oncotarget (2016) 7:5143-56
- Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T cell acute lymphoblastic leukemia.
Jost TR, Borga C, Radaelli E, Romagnani A, Perruzza L, Omodho L, Cazzaniga G, Biondi A, Indraccolo S, Thelen M, Te Kronnie G, Grassi F.
J Leukoc Biol (2016) 99:1077-87
- Enhancement of Muscle T Regulatory Cells and Improvement of Muscular Dystrophic Process in mdx Mice by Blockade of Extracellular ATP/P2X Axis.
Gazzerro E, Baldassari S, Assereto S, Fruscione F, Pistorio A, Panicucci C, Volpi S, Perruzza L, Fiorillo C, Minetti C, Traggiai E, Grassi F, Bruno C.
Am J Pathol (2015) 185:3349-60
- Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, D’Antuono R, Montani E, Garcia-Escudero R, Guccini I, Da Silva-Alvarez S, Collado M, Eisenberger M, Zhang Z, Catapano C, Grassi F, Alimonti A.
Nature (2014) 515:134-7
- ATP-gated ionotropic P2X7 receptor controls follicular T helper cell numbers in Peyer’s patches to promote host-microbiota mutualism.
Proietti M, Cornacchione V, Rezzonico Jost T, Romagnani A, Faliti CE, Perruzza L, Rigoni R, Radaelli E, Caprioli F, Preziuso S, Brannetti B, Thelen M, McCoy KD, Slack E, Traggiai E, Grassi F.
Immunity (2014) 41:789-801
- Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity.
Schena F, Volpi S, Faliti CE, Penco F, Santi S, Proietti M, Schenk U, Damonte G, Salis A, Bellotti M, Fais F, Tenca C, Gattorno M, Eibel H, Rizzi M, Warnatz K, Idzko M, Ayata CK, Rakhmanov M, Galli T, Martini A, Canossa M, Grassi F, Traggiai E.
Cell Rep (2013) 3:1824-31
- Purinergic P2X7 receptor drives T cell lineage choice and shapes peripheral gammadelta cells.
Frascoli M, Marcandalli J, Schenk U, Grassi F.
J Immunol (2012) 189:174-80
- Anti-CD3epsilon mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications.
Marrella V, Poliani PL, Fontana E, Casati A, Maina V, Cassani B, Ficara F, Cominelli M, Schena F, Paulis M, Traggiai E, Vezzoni P, Grassi F, Villa A.
Blood (2012) 120:1005-14
- Pharmacologic P2X purinergic receptor antagonism in the treatment of collagen-induced arthritis.
Ardissone V, Radaelli E, Zaratin P, Ardizzone M, Ladel C, Gattorno M, Martini A, Grassi F, Traggiai E.
Arthritis Rheum (2011) 63:3323-32
- Cell-autonomous regulation of hematopoietic stem cell cycling activity by ATP.
Casati A, Frascoli M, Traggiai E, Proietti M, Schenk U, Grassi F.
Cell Death Differ (2011) 18:396-404
- ATP inhibits the generation and function of regulatory T cells through the activation of purinergic P2X receptors.
Schenk U, Frascoli M, Proietti M, Geffers R, Traggiai E, Buer J, Ricordi C, Westendorf AM, Grassi F.
Sci Signal (2011) 4:ra12