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Molecular Immunology

Department of Evolutionary Biology
University of Siena
via Aldo Moro, 2 53100 Siena
Tel: +39 577 234396
Fax: +39 577 234476

Principal Investigator: Prof. Cosima T. Baldari

staff picture  Staff

  • Dr. Cristina Ulivieri, staff researcher
  • Dr. Silvia Rossi Paccani, staff researcher
  • Dr. Laura Patrussi, post-doctoral fellow
  • Dr. Michela Pellegrini, post-doctoral fellow
  • Dr. Francesca Finetti, PhD student
  • Dr. Daniela Benati, PhD student
  • Dr. Maria Teresa Savino, PhD student
  • Dr. Nagaja Capitani, PhD student
  • Dr. Daniela Fanigliulo, PhD student
  • Dr. Orso Maria Lucherini, PhD student
  • Dr. Dr. Micol Ferro, fellow
  • Dr. Annalisa Nuccitelli, fellow

Our Laboratory is focused on:

  1. the molecular dissection of signaling pathways in T cells
  2. the identification of signaling dysfunction in diseases related to immune system failure, i.e. lymphoproliferative pathologies, genetic immunodeficiencies and infections.

Main Research Themes

The research activity of the Unit covers the following topics, which all relate to signal transduction in lymphocytes:

  1. Functional characterization of the Shc protein family in lymphocytes.
    Among these activities, most relevant to cancer research is the study of Shc proteins, which we have first identified as key players in TCR and CD4 signaling to the small G-protein Ras. We have been able to associate this family of adaptor proteins with a number of cellular and physiological functions in T lymphocytes: p46Shc and p52Shc to the transduction of mitogenic stimuli and to the signaling machinery controlling actin cytoskeleton remodelling and chemotaxis, and p66Shc to oxidative stress-induced apoptosis and to inhibition of mitogenic stimuli. Moreover, we have identified a direct correlation between epigenetic modifications of p66Shc promoter and gene expression.
    Our current work on genetically modified mice lacking expression pf either p66Shc or the related protein ShcC/Rai is focused on the detailed analysis of the functions of these proteins in the immune system, with stress on their role in apoptosis and related pathologies, including lymphoproliferative disease and autoimmunity. Moreover, we are currently analyzing p66Shc expression and the epigenetic modification of its gene promoter in patients affected by chronic lymphotic leukaemia (B-CLL), who are characterized by impaired B-cell apoptosis.
  2. Identification of the genetic defect in primary immunodeficiencies
    Common variable immunodeficiency (CVID) is one of the most frequent genetic dysfunctions of the immune system. Patients share heterogeneous dysfunctions characterized by low circulating antibodies and leading to the alteration of immune responses and increased susceptibility to infections. We have reported that a subgroup of CVID patients shares defective transcription of the gene encoding Vav1, a protein involved in antigen-dependent signaling pathways in T cells. The decreased levels of this protein account at least in part for the defective cytoskeletal reorganization observed in these patients following antigenic stimulation.
    Preliminary results have provided evidence of a potential haploinsufficiency, and we are presently mapping the putative deletion of the Vav1 gene in CVID patients.
  3. Subversion in intracellular signaling as a strategy of immune evasion by pathogens
    The interest of our group in host/pathogen interactions has provided novel key information on the mechanism of immune evasion by pathogens, based on subversion of intracellular signaling. Our work in this field has resulted in the identification of two independent immunosuppressive activities of the Helicobacter pylori vacuolating cytotoxin (VacA), as well as in the identification of an effective mechanism of suppression of both innate and acquired immunity by Bacillus anthracis, the etiological agent of anthrax, based on the cooperative activity of the two anthrax toxins.
  4. Identification of drug targets in antigen receptor signaling pathways
    Our current research is focused on the study of the potential modulation of immune responses by the adenylate cyclase toxins of Bacillus anthracis and Bordetella pertussis.

    Finally, we have extensively studied the molecular targets of two families of drugs commonly used in the treatment of human diseases, non-steroidal anti-inflammatory drugs (NSAID) and statins. We have mapped the anti-inflammatory and immunosuppressive properties of NSAIDs within the T-cell antigen receptor signaling pathway. Furthermore, we have demonstrated that the widely used hypocholesterolemic drug simvastatin inhibits T-cell activation both directly and indirectly, by inhibiting antigen processing and presentation by B-cells and dendritic cells, through its capacity to impair prenylation of small Ras superfamily GTPases.
    We are currently studying the effects of simvastatin on opsonophagocytosis by macrophages and neutrophils. Moreover, we are studying the effects of immunosuppressive treatments in regulatory T cells from transplanted donors.

Research Grants

  • 2003-2006 MIUR (FIRB) Formal methods for biomolecular systems
  • 2004-2006 MIUR (PRIN)Mitochondria as mediators of T cell apoptosis and therapeutic targets in immunological diseases
  • 2002-2006 Eub Identification, presentation and delivery of epitopes for the development of novel vaccines for cytomegalovirus infection
  • 2006-2007 Telethon Genetic and biochemical characterization of CVID
  • 2006-2009 MIUR (FIRB int) Anthrax toxins and their role in the pathogenesis of the disease
  • 2004-2006 AIRC The Shc protein family in T cell activation, execution of effector functions and apoptosis
  • 2006-2008 MIUR (PRIN) Molecular and genetic dissection of the mitochondrial pathway of apoptosis

Publications

  1. Patrussi L, Ulivieri C, Lucherini OM, Rossi Paccani S, Gamberucci A, Lanfrancone L, Pelicci PG, Baldari, C.T. (2007). p52Shc is required for CXCR4-dependent signaling and chemotaxis in T-cells. Blood 2007 9, 924-929May 30; [Epub ahead of print]
  2. Rossi Paccani S, Tonello F, Patrussi L, Capitani N, Simonato M, Montecucco C, Baldari CT. Anthrax toxins inhibit immune cell chemotaxis by perturbing chemokine receptor signalling. Cell Microbiol. 2007. 9, 924-929. Epub 2006 Nov 3.
  3. Ghittoni R, Napolitani G, Benati D, Ulivieri C, Patrussi L, Laghi Pasini F, Lanzavecchia A, Baldari CT. Simvastatin inhibits the MHC class II pathway of antigen presentation by impairing Ras superfamily GTPases. Eur J Immunol. 2006 Nov;36(11):2885-93. Erratum in: Eur J Immunol. 2006 Dec;36(12):3381. Uliveri, Cristina [corrected to Ulivieri, Cristina].
  4. Pezzicoli A, Ulivieri C, Capitani N, Ventura A, Pelicci P, Baldari CT. Expression in T-cells of the proapoptotic protein p66SHC is controlled by promoter demethylation. Biochem Biophys Res Commun. 2006 Oct 13;349(1):322-8. Epub 2006 Aug 17.
  5. Baldari CT, Tonello F, Paccani SR, Montecucco C. Anthrax toxins: A paradigm of bacterial immune suppression. Trends Immunol. 2006 Sep;27(9):434-40. Epub 2006 Jul 24. Review.
  6. Pellegrini M, Finetti F, Petronilli V, Ulivieri C, Giusti F, Lupetti P, Giorgio M, Pelicci PG, Bernardi P, Baldari CT. p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis. Cell Death Differ. 2007 Feb;14(2):338-47. Epub 2006 Jun 23.
  7. Ulivieri C, Baldari CT. The BCR signalosome: where cell fate is decided. J Biol Regul Homeost Agents. 2005 Jan-Jun;19(1-2):1-16. Review.
  8. Paccani SR, Boncristiano M, Patrussi L, Ulivieri C, Wack A, Valensin S, Hirst TR, Amedei A, Del Prete G, Telford JL, D'Elios MM, Baldari CT. Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects. Blood. 2005 Jul 15;106(2):626-34. Epub 2005 Apr 7.
  9. Baldari CT, Lanzavecchia A, Telford JL. Immune subversion by Helicobacter pylori. Trends Immunol. 2005 Apr;26(4):199-207. Review.
  10. Pellegrini M, Pacini S, Baldari CT. p66SHC: the apoptotic side of Shc proteins. Apoptosis. 2005 Jan;10(1):13-8. Review.
  11. Paccani SR, Tonello F, Ghittoni R, Natale M, Muraro L, D'Elios MM, Tang WJ, Montecucco C, Baldari CT. Anthrax toxins suppress T lymphocyte activation by disrupting antigen receptor signaling. J Exp Med. 2005 Feb 7;201(3):325-31.
  12. Patrussi L, Savino MT, Pellegrini M, Paccani SR, Migliaccio E, Plyte S, Lanfrancone L, Pelicci PG, Baldari CT. Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T-cell antigen receptor signaling to Ras family GTPases and Myc-dependent survival. Oncogene. 2005 Mar 24;24(13):2218-28.
  13. Ghittoni R, Patrussi L, Pirozzi K, Pellegrini M, Lazzerini PE, Capecchi PL, Pasini FL, Baldari CT. Simvastatin inhibits T-cell activation by selectively impairing the function of Ras superfamily GTPases. FASEB J. 2005 Apr;19(6):605-7. Epub 2005 Jan 27.
  14. Baldari CT, Koretzky G, Telford JL, Acuto O. Antigen receptor signaling: the Tuscan chronicles. Nat Immunol. 2005 Jan;6(1):3-5.
  15. Paccani SR, Patrussi L, Ulivieri C, Masferrer JL, D'Elios MM, Baldari CT. Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling Blood. 2005 Mar 1;105(5):2042-8. Epub 2004 Oct 28.
  16. Pacini S, Pellegrini M, Migliaccio E, Patrussi L, Ulivieri C, Ventura A, Carraro F, Naldini A, Lanfrancone L, Pelicci P, Baldari CT. p66SHC promotes apoptosis and antagonizes mitogenic signaling in T cells. Mol Cell Biol. 2004 Feb;24(4):1747-57.
  17. Boncristiano M, Paccani SR, Barone S, Ulivieri C, Patrussi L, Ilver D, Amedei A, D'Elios MM, Telford JL, Baldari CT. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med. 2003 Dec 15;198(12):1887-97.
  18. Rossi Paccani S, Boncristiano M, Baldari CT. Molecular mechanisms underlying suppression of lymphocyte responses by nonsteroidal antiinflammatory drugs. Cell Mol Life Sci. 2003 Jun;60(6):1071-83. Review.
  19. Ulivieri C, Valensin S, Majolini MB, Matthews RJ, Baldari CT. Normal B-1 cell development but defective BCR signaling in Lck-/- mice. Eur J Immunol. 2003 Feb;33(2):441-5.
  20. Baldari CT. Antigen receptor signaling under the Tuscan sun. Nat Immunol. 2002 Nov;3(11):1053-5.
  21. Bini L, Pacini S, Liberatori S, Valensin S, Pellegrini M, Raggiaschi R, Pallini V, Baldari CT. Extensive temporally regulated reorganization of the lipid raft proteome following T-cell antigen receptor triggering. Biochem J. 2003 Jan 15;369(Pt 2):301-9.
  22. Valensin S, Paccani SR, Ulivieri C, Mercati D, Pacini S, Patrussi L, Hirst T, Lupetti P, Baldari CT. F-actin dynamics control segregation of the TCR signaling cascade to clustered lipid rafts. Eur J Immunol. 2002 Feb;32(2):435-46.
  23. Paccani SR, Boncristiano M, Ulivieri C, D'Elios MM, Del Prete G, Baldari CT. Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction. J Biol Chem. 2002 Jan 11;277(2):1509-13. Epub 2001 Nov 7.
  24. Plyte S, Boncristiano M, Fattori E, Galvagni F, Paccani SR, Majolini MB, Oliviero S, Ciliberto G, Telford JL, Baldari CT. Identification and characterization of a novel nuclear factor of activated T-cells-1 isoform expressed in mouse brain. J Biol Chem. 2001 Apr 27;276(17):14350-8. Epub 2001 Jan 24.
  25. Ulivieri C, Peter A, Orsini E, Palmer E, Baldari CT. Defective signaling to Fyn by a T cell antigen receptor lacking the alpha -chain connecting peptide motif. J Biol Chem. 2001 Feb 2;276(5):3574-80. Epub 2000 Oct 31

Collaborations

  • Prof. Francesco Lauria. Division of Hematology and Transplants, Department of Medicine and Immunological Sciences, University of Siena, Siena, Italy
  • Prof. Lorenzo Leoncini. Department of Clinical Medicine and Immunological Sciences, Section of Dermatology, University of Siena, Italy.
  • Prof. Pier Giuseppe Pelicci. European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy
  • Prof. Paolo Bernardi. Department of Biomedical Sciences, University of Padova, Viale Giuseppe Colombo 3, I-35121, Padova, Italy
  • Prof. Cesare Montecucco. Department of Biomedical Sciences, University of Padua, Via Trieste 75, 35121 Padua, Italy.
  • Dr. John L. Telford. Novartis Vaccines and Diagnostics Srl, Via Fiorentina 1, 53100, Siena, Italy.
  • Prof. Gianfranco Del Prete. Department of Internal Medicine, University of Florence, Viale Morgagni 85, 50134 Florence, Italy.
  • Dr. R. James Matthews. Section of Infection and Immunity, University of Wales, College of Medicine, Cardiff, GB
  • Dr. R. Jaime Masferrer. Pfizer Research, Chesterfield, Missouri (USA)
  • Prof. Franco Laghi Pasini. Department of Clinical Medicine and Immunological Sciences, Policlinico Le Scotte, University of Siena, Siena, Italy
  • Prof. Antonio Lanzavecchia. Institute for Research in Biomedicine, Bellinzona, Switzerland.