Mechanisms of peripheral tolerance
Main interest of the Unit is to unravel the key molecular and cellular mechanisms controlling immune tolerance. The Unit aims at studying and modulating antigen(Ag)-specific immune responses, to develop efficient therapeutic approaches to (re)establish antigen-specific immune tolerance or to boost immunity in T-cell mediated diseases.
The group focused his research on IL-10-secreting regulatory cells and contributed to the identification of DC-10 that ara present in vivo and inducible in vitro. DC-10 are tolerogenic DC that secrete IL-10 and express HLA-G and ILT4, which render them inducers of Tr1 cells. We are currently involved in defining the role of DC-10 in control immune responses healthy and pathological conditions.
Moreover, the group developed an innovative approach, based on Lentiviral Vector (LV)- mediated gene transfer to generate stable and effective human DC suitable for cell-based approaches in immune-mediated diseases. We are currently testing engineered DC in pre-clinical models in vivo and on human samples in vitro. Immune cell identity, cell fate, and functional stability are not only controlled by the expression of transcription factors, but rather determined and maintained by epigenetic modifications. Thus far, chromatin remodeling and expression of specific non-coding RNA have been studied in human T cells, including Tregs, but only limited data are available for human DC, and especially tolerogenic DC. Given the key role of epigenetics in controlling cell identity/plasticity, the group is also investigating the epigenetic landscape of tolerogenic DC and Tregs.
Finally, a number of projects aimed at understanding/modulating immune responses to specific transgenes are active in the lab. Among those, we are actively collaborating on projects aimed at defining the impact of pre-existing immune responses on ex vivo and in vivo gene therapy.
Roncarolo MG, Gregori S, Bacchetta R, Battaglia M, Gagliani N. The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases. Immunity. 2018 Dec 18;49(6):1004-1019.
Amodio G, Cichy J, Conde P, Matteoli G, Moreau A, Ochando J, Oral BH, Pekarova M, Ryan EJ, Roth J, Sohrabi Y, Cuturi MC, Gregori S. Role of myeloid regulatory cells (MRCs) in maintaining tissue homeostasis and promoting tolerance in autoimmunity, inflammatory disease and transplantation. Cancer Immunol Immunother. 2018 Oct 24.
Comi M, Amodio G, Gregori S. Interleukin-10- Producing DC-10 Is a Unique Tool to Promote Tolerance Via Antigen-Specific T Regulatory Type 1 Cells. Front Immunol. 2018 Apr 6;9:682.
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