Immunometabolism

Team

Rottoli Elsa, PhD student, elsa.rottoli@unimi.it
Faliti Caterina Elisa, PhD student faliti@ingm.org

Scientific Background

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. Our research is aimed at understanding the role played by purinergic receptors in regulating T cell functions, namely responsiveness to T cell receptor (TCR) stimulation and other proliferative cues as well as gene expression and fate determination at various stages of development. Purinergic receptors include non-selective cationic channels (named P2X) and G protein coupled receptors (named P2Y). In the T cell the P2X7 receptor is the most abundantly expressed subtype, and has profound impact on T cell responsiveness and metabolism. Prolonged P2X7 stimulation or high concentration of ATP determine the opening of a pore permeable to molecules up to 900 Da and cell death. P2X7 transcription is developmentally regulated in T cells. We are currently studying the role of P2X7 in regulating T cell homeostasis and adaptive immunity in different physiological and pathological conditions. In particular, we are addressing the impact of P2X7 activity in metabolic reprogramming of the T cell and in regulating T cell effector functions. Our results point to a crucial role of P2X7 in the physiological control of CD4 T cell responsiveness. On the one hand, this receptor constitutes a promising target for modulating T cell function in autoimmune conditions; on the other hand P2X7 pharmacological antagonism could be exploited for improving T cell effector functions.

Ongoing Projects

  1. Role of the ATP-gated ionotropic P2X7 receptor in T cell function.
  2. Purinergic regulation of T follicular helper cells in systemic lupus erythematosus.

Related Publications

Role of CXCR4-mediated bone marrow colonization in CNS infiltration by T-cell acute lymphoblastic leukemia.
Rezzonico-Jost T., Borga C., Radaelli E., Romagnani A., Perruzza L., Omodho L., Cazzaniga G., Biondi A., Indraccolo S., Thelen M., te Kronnie G. and Grassi F.
Journal of Leukocyte Biology, in press (2016)

Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects.
Rigoni R., Fontana E., Guglielmetti S., Fosso B., D’Erchia A.M., Maina V., Taverniti V., Castiello M.C., Mantero S., Pacchiana G., Musio S., Pedotti R., Selmi C., Mora J.R., Pesole G., Vezzoni P., Poliani P.L., Grassi F., Villa A. and Cassani B.
The Journal of Experimental Medicine, 213: 355-375 (2016)

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. and Grassi F.
Oncotarget, 7: 5143-5156 (2016)

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 and Bruno C.
The American Journal of Pathology, 185: 3349-3360 (2015)xx

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 C.E., Perruzza L., Rigoni R., Radaelli E., Caprioli F., Preziuso S., Brannetti B., Thelen M., McCoy K.D., Slack E., Traggiai E. and Grassi F.
Immunity, 41: 789-801 (2014)

Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
Di Mitri D., Toso A., Chen J.J., Sarti M., Pinton S., Rezzonico-Jost T., D’Antuono R., Montani E., Garcia-Escudero R., Guccini I., Da Silva-Alvarez S., Collado M., Eisenberger M., Zheng Z., Catapano C., Grassi F. and Alimonti A.
Nature, 515: 134-137 (2014).

Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity.
Toso A., Revandkar A., Di Mitri D., Guccini I., Proietti M., Sarti M., Pinton S., Zhang J., Kalathur M., Civenni G., Jarrossay D., Montani E., Marini C., Garcia-Escudero R., Scanziani E., Grassi F., Pandolfi P.P., Catapano C.V. and Alimonti A.
Cell Reports, 9: 75-89 (2014).

Dependence of immunoglobulin class switch recombination in B cells on vesicular release of ATP and CD73 ectonucleotidase activity.
Schena F., Volpi S., Faliti C.E., Penco F., Santi S., Proietti M., Schenk U., Damonte G., Salis A., Bellotti M., Fais F., Tenca C., Martini A., Gattorno M., Eibel H., Rizzi M., Warnatz K., Idzko M., Ayata K., Rakhmanov M., Galli T., Canossa M., Grassi F. and Traggiai E.
Cell Reports, x3: 1824-1831 (2013).xx

Remote system for monitoring animal models with single-metabolite bio-nano-sensors.
Carrara S., Bolomey L., Boero C., Cavallini A., Meurville E., De Micheli G., Rezzonico Jost T., Proietti M. and Grassi F.
IEEE Sensors Journal, 13: 1018-1024 (2013)

Effect of the purinergic inhibitor oxidized-ATP in a model of islet allograft rejection.
Vergani A., Fotino C., D’Addio F., Tezza S., Podetta M., Gatti F., Chin M., Bassi R., Molano R.D., Corradi D., Gatti R., Ferrero M.E., Secchi A., Grassi F., Ricordi C., Sayegh M.H., Maffi P., Pileggi A. and Fiorina P.
Diabetes, 62: 1665-1675 (2013)

Long-term heart transplant survival by targeting the ionotropic purinergic receptor P2X7.
Vergani A., Tezza S., D’Addio F., Fotino C., Liu K., Niewczas M., Bassi R., Molano R.D., Kleffel S., Petrelli A., Soleti A., Ammirati E., Frigerio M., Visner G., Grassi F., Ferrero M.E., Corradi D., Abdi R., Ricordi C., Sayegh M.H., Pileggi A., Fiorina P.
Circulation, 127: 463-475 (2013)

Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn: therapeutic implications.
Marrella V., Poliani P.L., Fontana E., Casati A., Maina V., Cassani B., Ficara F., Cominelli M., Schena F., Paulis M., Traggiai E., Vezzoni P., Grassi F. and Villa A. syndrome: therapeutic implications.
Blood, 120: 1005-1014 (2012)

Purinergic P2X7 receptor drives T cell lineage choice and shapes peripheral γδ cells.
Frascoli M., Marcandalli J., Schenk U. and Grassi F.
The Journal of Immunology, 189: 174-180 (2012)

Phenotypic analysis and isolation of murine hematopoietic stem cells and lineage committed progenitors.
Frascoli M., Proietti M. and Grassi F.
Journal of Visualized Experiments, 65: e3736 (2012).

Development of tertiary lymphoid structures in the kidneys of pigs with chronic leptospiral nephritis.
Pezzolato M., Maina E., Lonardi S., Bozzetta E., Grassi F., Scanziani E. and Radaelli E.
Veterinary Immunology and Immunopathology, 145: 546-550 (2012)

Pharmacological purinergic P2X antagonism in the treatment of experimental collagen-induced arthritis.
Ardissone V., Radaelli E., Zaratin P., Ardizzone M., Ladel C., Gattorno M., Martini A., Grassi F. and Traggiai E.
Arthritis & Rheumatism, 63: 3323-3332 (2011)

Indoleamine 2,3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells.
Pallotta M.T., Orabona C., Volpi C., Vacca C., Belladonna M.L., Bianchi R., Servillo G., Brunacci C., Calvitti M., Bicciato S., Mazza E.M.C., Boon L., Grassi F., Fioretti M.C., Fallarino F., Puccetti P. and Grohmann U.
Nature Immunology, 12: 870-878 (2011)

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 A.M. and Grassi F.
Science Signaling, 4: ra12 (2011)

Cell-autonomous regulation of hematopoietic stem cell cycling activity by ATP.
Casati A., Frascoli M., Traggiai E., Proietti M., Schenk U. and Grassi F.
Cell Death & Differentiation, 18: 396-404 (2011)

Selective preservation of bone marrow mature recirculating but not marginal zone B cells in murine models of chronic inflammation.
Traggiai E., Casati A., Frascoli M., Porcellini S., Ponzoni M., Sanvito F., Leng L., Bucala R., Moretta L. and Grassi F.
PLoS ONE 5(6): e11262. doi:10.1371/journal.pone.0011262 (2010)

Homeostatic expansion of autoreactive immunoglobulin secreting cells in the Rag2 mouse model of Omenn Syndrome.
Cassani B., Poliani P.L., Marrella V., Schena F., Sauer A.V., Ravanini M., Strina D., Busse C.E., Regenass S., Wardemann H., Martini A., Facchetti F., van der Burg M., Rolink A.G., Vezzoni P., Grassi F., Traggiai E. and Villa A.
The Journal of Experimental Medicine, 207: 1525-1540 (2010)

Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF.
Dolcetti L., Peranzoni E., Ugel S., Marigo I., Fernandez Gomez A., Mesa C., Geilich M., Winkels G., Traggiai E., Casati A., Grassi F. and Bronte V.
European Journal of Immunology, 40: 22-35 (2010)

Purinergic control of T cell activation by ATP released through pannexin-1 hemichannels.
Schenk U., Westendorf A.M., Radaelli E., Casati A., Ferro M., Fumagalli M., Verderio C., Buer J., Scanziani E. and Grassi F.
Science Signaling, 1 (39), ra6 (2008)

Recombinase-deficient T cell development by selective accumulation of CD3 into lipid rafts.
Ferrera D., Panigada M., Porcellini S. and Grassi F.
European Journal of Immunology, 38:1148-1156 (2008)

A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome.
Marrella V., Poliani P.L., Casati A., Rucci F., Frascoli L., Gougeon M-L., Lemercier B., Bosticardo M., Ravanini M., Battaglia M., Roncarolo M.G., Cavazzana-Calvo M., Facchetti F., Notarangelo L.D., Vezzoni P., Grassi F. and Villa A.
Journal of Clinical Investigation, 117: 1260-1269 (2007)

Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling.
Campese A.F., Garbe A.I., Zhang F., Grassi F., Screpanti I. and von Boehmer H.
Blood, 108: 305-310 (2006)

Regulation of peripheral T cell activation by calreticulin.
Porcellini S., Traggiai E., Schenk U., Ferrera D., Matteoli M., Lanzavecchia A., Michalak M. and Grassi F.
The Journal of Experimental Medicine, 203: 461-471 (2006)

INGM researches are supported by