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. In particular, the Unit aims at studying and modulating antigen(Ag)-specific immune responses, in order to develop efficient therapeutic approaches to (re)establish antigen-specific immune tolerance in T cell mediated diseases including allogeneic bone marrow and solid organ transplantation, autoimmune diseases, allergy, and gene therapy. Several cell subsets have been described to participate to establishment of immune tolerance and proposed as cell therapy tools to mediate inverse vaccination. Together with the more studied regulatory T cells (both Type 1 - Tr1 - and CD25+FOXP3+ - Treg), growing evidence indicates that different subsets of dendritic cells (DC), either naturally arising or experimentally induced, play a critical role in promoting immune tolerance.
Our group has contributed to the identification and the characterization of a subset of cells, named DC-10, present in vivo and inducible in vitro from peripheral blood monocytes in the presence of IL-10. DC-10 are potent tolerogenic DC characterized by the ability to secrete high amounts of IL-10, and by the expression of immunomodulatory molecules including HLA-G, ILT3, and ILT4, which render them potent inducers of Ag-specific Tr1 cells in vitro (Amodio et al., 2015; Gregori et al., 2010). Interestingly, stimulation of allergen-specific T cells with autologous DC-10 promotes their conversion into IL-10-producing suppressive T cells (Pacciani et al., 2010), indicating that DC-10 represent a good candidate to convert effector T cells into regulatory T cells. In the past years, we have also elucidated the mechanisms underlying the induction and functions of Tr1 cells, an inducible subset of CD4+ T regulatory cells characterized by the ability to secrete IL-10 and to suppress T cell responses in vitro and in vivo via IL-10 and TGF-β secretion. These studies have been instrumental to the definition of a modified protocol for the induction of Tr1 cells for cell therapy currently under clinical development. For the first time we have also showed that specific killing of myeloid cells represents an additional mechanism of suppression mediated by Tr1 cells. In collaboration with the group led by Prof. Maria Grazia Roncarolo, we have contributed to the definition of a new protocol for the induction of Tr1 cells in vitro by lentiviral-vector mediated IL-10 gene transfer into CD4+ T cells and to the discovery of specific biomarkers of Tr1 cells, which allows their identification and isolation (Andolfi et al., 2012; Gagliani et al., 2013). In collaboration with Dr. Rosa Bacchetta, we have also contributed to the characterization of CD25+FOXP3+ Treg cells in healthy and pathological settings and to the development of a protocol based on lentiviral-vector mediated gene transfer of FOXP3 into CD4+ T cells for the induction of Treg-like cells (Passerini et al., 2013). Finally, Andrea Annoni, project leader in the Unit, has developed and characterized in Maria Grazia Roncarolo’s group a lentiviral vector-based platform able to induce antigen-specific tolerance in vivo (Annoni et al. 2017 and 2009).