Regulation of host-microbiota interaction by the adaptive immune systemegulation 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, extracellular ATP (eATP) acts as a signalling molecule 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. P2rx7 expression is robustly upregulated in T follicular helper (Tfh) cells and in the intestine, eATP released by commensal bacteria conditions Tfh cell activity and the generation of secretory IgA (SIgA), which in turn shapes microbiota structure. Since the microbiota plays a crucial role in most functions of the organism, we are studying SIgA mediated adaptation of the gut ecosystem in different pathophysiological conditions, in particular in dysbiosis during cancer immunotherapy, antibiotic treatments and unhealthy diets.
Projects
- Probing gut-tumor axis during immune checkpoint blockade
- The secretory IgA repertoire in intestinal homeostasis
Team
| Nome / Name | Ruolo / Role | |
|---|---|---|
| Rebecca Marino | Student | rebecca.marino@studenti.unimi.it |
| Gaia Salina | Student | gaia.salina98@gmail.com |
Publications
- mTOR-dependent translation drives tumor infiltrating CD8+ effector and CD4+ Treg cells expansion.
De Ponte Conti B., Miluzio A., Grassi F., Abrignani S., Biffo S., Ricciardi S.
eLife, 10: e69015 (2021) - Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis.
Pernigoni N., Zagato E., Calcinotto A., Troiani M., Mestre R.P., Cali B., Attanasio G., Troisi J., Minini M., Mosole S., Revandkar A., Pasquini E., Elia A.R., Bossi D., Rinaldi A., Rescigno P., Flohr P., Hunt J., Neeb A., Buroni L., Guo C., Welti J., Ferrari M., Grioni M., Gauthier J., Gharaibeh R.Z., Palmisano A., Lucchini G.M., D’Antonio E., Merler S., Bolis M., Grassi F., Esposito A., Bellone M., Briganti A., Rescigno M., Theurillat J.P., Jobin C., Gillessen S., de Bono J., Alimonti A. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis.
Science, 374: 216-224 (2021) - P2X7 receptor activity limits accumulation of T cells within tumors.
Romagnani A., Rottoli E., Mazza E.M.C., Rezzonico-Jost T., De Ponte Conti B., Proietti M., Perotti M., Civanelli E., Perruzza L., Catapano A.L., Baragetti A., Tenedini E., Tagliafico E., Falzoni S., Di Virgilio F., Norata G.D., Bicciato S. and Grassi F.
Cancer Research, 80: 3906-3919 (2020) - Prophylactic activity of orally Administered FliD-reactive monoclonal SIgA against Campylobacter infection.
Perruzza L., Jaconi S., Lombardo G., Pinna D., Strati F., Morone D., Seehusen F., Hu Y., Bajoria S., Xiong J., Kumru O.S., Joshi S.B., Volkin D.B., Piantanida R., Benigni F., Grassi F., Corti D., Pizzuto M.S.
Frontiers in Immunology, 11: 1011 (2020) - Enrichment of intestinal Lactobacillus by enhanced secretory IgA coating alters glucose homeostasis in P2rx7-/- mice.
Perruzza L., Strati F., Gargari G., D’Erchia A.M., Fosso B., Pesole G., Guglielmetti S. and Grassi F.
Scientific Reports, 9: 9315 (2019) - P2X7 receptor restrains pathogenic Tfh cell generation in systemic lupus erythematosus.
Faliti C.E., Gualtierotti R., Rottoli E., Gerosa M., Perruzza L., Romagnani A., Pellegrini G., De Ponte Conti B., Rossi R. L., Idzko M., Mazza E. M. C., Bicciato S., Traggiai E., Meroni P. L. and Grassi F.
The Journal of Experimental Medicine, 216: 317-336 (2019) - ATP released by intestinal bacteria limits the generation of protective IgA against enteropathogens.
Proietti M., Perruzza L., Scribano D., Pellegrini G., D’Antuono R., Strati F., Raffaelli M., Gonzalez S. F., Thelen M., Hardt W. D., Slack E., Nicoletti M. and Grassi F.
Nature Communications, 10:250, doi: 10.1038/s41467-018-08156-z (2019) - TRPM7 kinase activity is essential for T cell colonization and alloreactivity in the gut.
Romagnani A., Vettore V., Rezzonico-Jost T., Hampe S., Rottoli E., Nadolni W., Perotti M., Meier M.A., Hermanns C., Geiger S., Wennemuth G., Recordati C., Matsushita M., Muehlich S., Proietti M., Chubanov V., Gudermann T., Grassi F. and Zierler S.
Nature Communications, 8:1917, doi: 10.1038/s41467-017-01960-z (2017) - 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.
Cell Rep (2017) 18:2566-2575
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