Mechanisms of peripheral tolerance
Main interest of the Unit is to unravel the key molecular and cellular mechanisms controlling immune tolerance, responsible for maintaining tissue homeostasis and avoiding adverse immune responses. The Unit aims at studying and modulating antigen(Ag)-specific immune responses, to develop efficient therapeutic approaches to (re)establish Ag-specific immune tolerance in allogeneic bone marrow and solid organ transplantation, autoimmune diseases, allergy, and gene therapy. Together with the more studied regulatory T cells (Tr1 and CD25+FOXP3+ Treg), growing evidence indicates that different subsets of dendritic cells (DC), play a critical role in promoting immune tolerance.
In collaboration with the group led by Prof. Roncarolo, this unit contributed to the definition of protocols for the induction of Tr1 cells for cell-based approaches and to the discovery of specific biomarkers of Tr1 cells. In collaboration with Dr. Bacchetta, this unit also contributed to the characterization of CD25+FOXP3+ Treg cells in healthy and pathological settings and to the development of a protocol to generate them based on gene transfer of FOXP3. Finally, Dr. Annoni has developed and characterized in Maria Grazia Roncarolo’s group a lentiviral vector-based platform able to induce antigen-specific tolerance in vivo.
Locafaro G*, Andolfi G*, Russo F, Camisa B, Ciceri F, Bondanza A, Roncarolo MG*, Gregori S. HLA class I-dependent targeting of myeloid leukemia by IL-10-engineered human CD4+ Tr1 cells. Mol Ther. 2017 Oct 4;25(10):2254-2269. *Equal contributors.
Trzonkowski P, Bacchetta R, Battaglia M, Berglund D, Bohnenkamp R-H, ten Brinke A, Bushell A, Cools N, Geissler E, Gregori S, Mvan Ham SM, Hilkens C, Hutchinson J, Lombardi G, Madrigal J-A, Trzonkowska N-M, Martínez Cáceres EM, Roncarolo MG, Sanchez-Ramon S, Saudemont A, Sawitzki B. On the hurdles in therapy with T regulatory cells. Sci Transl Med. 2015 Sep 9;7(304):304ps18. *All authors equally contributed to this study.
Amodio G., Comi M., Tomasoni D., Gianolini M.E. , Rizzo R., LeMaoult J., Roncarolo M-G., and Gregori S. HLA-G expression levels influence the tolerogenic activity of human DC-10. Haematologica. 2015 Apr;100(4):548-57.
Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, De’Broski H, Bulfone A, Bacchetta R, Andreani M, Gregori S*, Flavell R*, Roncarolo MG*. Co-expression of CD49b and LAG-3 identifies human and murine Tr1 cells. Nat Med. 2013 Jun;19(6):739-46. *Equal contributors.
Andolfi G, Fousteri G, Rossetti M, Magnani CF, Jofra T, Locafaro G, Bondanza A, Gregori S*, Roncarolo MG*. Enforced IL-10 expression confers type 1 regulatory T cell (Tr1) phenotype and function to human CD4(+) T cells. Mol Ther. 2012 Sep;20(9):1778-90. *Equal contributors.
Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S. Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol. 2011 Jun;41(6):1652-62.
Bacchetta R*, Gregori S*, Serafini G, Sartirana C, Schulz U, Zino E, Tomiuk S, Jansen U, Ponzoni M, Paties CT, Fleischhauer K, Roncarolo MG. Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy. Haematologica 2010 Dec;95(12):2134-43. *Equal contributors.
Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, Hauben E, Roncarolo MG. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood. 2010 Aug 12;116(6):935-44.
Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1a,25- dihydroxyvitamin D3 analog enhanced regulatory T cells and arrests autoimmune diabetes in NOD mice. Diabetes 2002, May;51(5):1367-74.
Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by MMF/1,25(OH)2D3 treatment mediate transferable transplantation tolerance. J. Immunol. 2001, Vol. 167: 1945-53.
Francesca Santino De Sio