Regulation of adaptive immunity
Our team studies the mechanisms that control autoimmunity. We investigate the genetic and cellular factors that set the immune system in equilibrium. We also develop innovative approaches to promote tolerance in patients with type 1 diabetes (T1D) by genetically engineering regulatory T cells (Treg).
We aim at:
- Deciphering the genetic secrets of T1D for better disease diagnosis and prediction. Our group employs cutting-edge technologies to identify possible genetic changes in T1D, to help diagnose the disease more accurately and improve its prediction. Our objective is to understand how some of these changes affect the immune system and the function of insulin-producing cells.
- Understanding islet-specific autoantibody pathogenesis in T1D. Our goal is to understand the process of generating islet-specific autoantibodies in patients with T1D. We study two populations of cells, follicular helper (Tfh) and follicular regulatory (Tfr) CD4 T cells that are uniquely specialized in providing B-cell help and regulating this process, respectively.
- Immune therapy with regulatory T cells to establish tolerance in T1D. Adoptive cell therapy with Treg cells stands out as one of the most promising therapeutic strategies to treat autoimmunity. In collaboration with Prof Chiara Bonini from San Raffaele and Prof Todd Brusko of the University of Florida, we aim to create a new class of antigen-specific Treg cells that would combat the activation of B cells.
- Primary immunodeficiencies: follicular helper and follicular regulatory T cells as disease biomarkers and therapeutic targets. Several primary immunodeficiencies of known and unknown genetic origin are characterized by B cell deficiency and /or production of autoantibodies. In collaboration with Dr. Maria Pia Cicalese (group of Prof Alessandro Aiuti) and Carmen Castiello (group of Prof. Anna Villa) we are studying the cause of the humoral defects in these patients by analyzing their Tfh and Tfr cell compartment.
Vecchione A, Gerosa J, Di Fonte R, Jofra T, Cicalese MP, Napoleone V, Ippolito E, Galvani G, Ragogna F, Stabilini A, Bianconi E, Grogan P, Bonura C, Bonfanti R, Frontino G, Nano R, Melzi R, De Pellegrin M, Laurenzi A, Meschi F, Barera G, Rigamonti A, Indirli R, Bosi E, Piemonti L, Aiuti A, Battaglia M, Fousteri G. Reduced PD-1 expression on circulating follicular and conventional FOXP3+ Treg cells in children with new onset type 1 diabetes and autoantibody-positive at-risk children. Clinical Immunol., 2019, in press.
De Leo P, Gazzurelli L, Baronio M, Montin D, Di Cesare S, Giancotta C, Licciardi F, Cancrini C, Aiuti A, Plebani A, Cicalese MP, Lougaris V, Fousteri G. NFKB2 regulates human Tfh and Tfr pool formation and germinal center potential. Clin Immunol., 2019, Nov 18;210:108309 (PMID: 31751612)
Fousteri G, Dave Jhatakia A. Viral Infections and Autoimmune Disease: Roles of LCMV in Delineating Mechanisms of Immune Tolerance. Viruses, 2019, Sep 21;11(10). pii: E885 (PMID: 31546586)
Jofra T, Galvani G, Cosorich I, De Giorgi L, Annoni A, Vecchione A, Sorini C, Falcone M, Fousteri G. Experimental colitis in IL-10-de cient mice ameliorates in the absence of PTPN22. Clin Exp Immunol., 2019, Jun 13. (PMID: 31194881)
Cicalese MP*, Gerosa, J*, Baronio M Montin D, Licciardi F, Soresina A, Dellepiane MR, Miano M, Baselli LA, Volpi S, Dufour C,Plebani A,Aiuti A, Lougaris V and Fousteri G. Circulating follicular helper and follicular regulatory T cells are severely compromised in human CD40 deficiency. Frontiers in Immunology, 2019, *Authors contributed equally.
Fabbri M, Frixou M and Fousteri G. Type 1 diabetes in STAT protein family mutations: Regulating the Th17/Treg equilibrium and beyond. Perspective. Diabetes, 2019; 68(2):258-265.
T. Jofra, R. Di Fonte, G. Galvani, M. Kuka, M. Iannacone, M. Battaglia and G. Fousteri, Tr1 cell immunotherapy promotes transplant tolerance via de novo Tr1 cell induction in mice and is safe and effective during acute viral infection, Eur J Immunol, 2018, Selected for the "In this issue" section of EJI.
G. Sebastiani, G. Ventriglia, A. Stabilini, C. Socci, C. Morsiani, A. Laurenzi, L. Nigi, C. Formichi, B. Mfarrej, A. Petrelli, G. Fousteri, T.M. Brusko, F. Dotta, M. Battaglia, Regulatory T-cells from pancreatic lymphnodes of patients with type-1 diabetes express increased levels of microRNA miR-125a-5p that limits CCR2 expression, Sci Rep, 7 (2017) 6897.
T. Jofra, G. Galvani, M. Kuka, R. Di Fonte, B.G. Mfarrej, M. Iannacone, S. Salek-Ardakani, M. Battaglia and G. Fousteri, Extrinsic Protein Tyrosine Phosphatase Non-Receptor 22 Signals Contribute to CD8 T Cell Exhaustion and Promote Persistence of Chronic Lymphocytic Choriomeningitis Virus Infection, Front Immunol, 8 (2017) 811.
J. Gerosa, V. Lougaris, M. Baronio, A. Plebani, M.P. Cicalese and G. Fousteri, Beta2 integrins are required for follicular helper T cell differentiation in humans, Clin Immunol, 180 (2017) 60-62. 7. Jofra T, Di Fonte R, Hutchinson TE, Dastmalchi F, Galvani G, Battaglia M, Salek- Ardakani S, Fousteri G: Protein tyrosine phosphatase PTPN22 has dual roles in promoting pathogen versus homeostatic-driven CD8 T-cell responses. Immunol Cell Biol 2016
Cantarelli E, Citro A, Pellegrini S, Mercalli A, Melzi R, Dugnani E, Jofra T, Fousteri G, Mondino A, Piemonti L: Transplant Site Influences the Immune Response After Islet Transplantation: Bone Marrow vs Liver. Transplantation, 2016
Fousteri G, Ippolito E, Ahmed R, Hamad AR: Beta-cell specific autoantibodies: Are they just an indicator of type 1 diabetes? Curr Diabetes Rev, 2016
Hamad AR, Ahmed R, Donner T, Fousteri G: B cell-targeted immunotherapy for type 1 diabetes: What can make it work? Discov Med, 2016; 21:213- 219
Di Fonte R, Baronio M, Plebani A, Lougaris V, Fousteri G: Reduced germinal center follicular helper T cells but normal follicular regulatory T cells in the tonsils of a patient with a mutation in the PI3KR1 gene. Clin Immunol, 2016;164:43-44
Fousteri G, Jofra T, Di Fonte R, Battaglia M: Combination of an Antigen-Specific Therapy and an Immunomodulatory Treatment to Simultaneous Block Recurrent Autoimmunity and Alloreactivity in Non-Obese Diabetic Mice. PLoS One, 2015;10:e0127631
Fousteri G, Jofra T, Di Fonte R, Gagliani N, Morsiani C, Stabilini A, Battaglia M: Lack of the protein tyrosine phosphatase PTPN22 strengthens transplant tolerance to pancreatic islets in mice. Diabetologia, 2015;58:1319-1328
Fousteri G, Jofra T, Di Fonte R, Kuka M, Iannacone M, Battaglia M: PTPN22 controls virally- induced autoimmune diabetes by modulating cytotoxic T lymphocyte responses in an epitope- specific manner. Clin Immunol 2015;156:98-108
Fousteri G, Jofra T, Debernardis I, Stanford SM, Laurenzi A, Bottini N, Battaglia M: The protein tyrosine phosphatase PTPN22 controls forkhead box protein 3 T regulatory cell induction but is dispensable for T helper type 1 cell polarization. Clin Exp Immunol 2014;178:178-189