title: Transplant tolerance to pancreatic islets is initiated in the graft and sustained in the spleen.
abstract: The immune system is comprised of several CD4(+) T regulatory (Treg) cell types, of which two, the Foxp3(+) Treg and T regulatory type 1 (Tr1) cells, have frequently been associated with transplant tolerance. However, whether and how these two Treg-cell types synergize to promote allograft tolerance remains unknown. We previously developed a mouse model of allogeneic transplantation in which a specific immunomodulatory treatment leads to transplant tolerance through both Foxp3(+) Treg and Tr1 cells. Here, we show that Foxp3(+) Treg cells exert their regulatory function within the allograft and initiate engraftment locally and in a non-antigen (Ag) specific manner. Whereas CD4(+) CD25(-) T cells, which contain Tr1 cells, act from the spleen and are key to the maintenance of long-term tolerance. Importantly, the role of Foxp3(+) Treg and Tr1 cells is not redundant once they are simultaneously expanded/induced in the same host. Moreover, our data show that long-term tolerance induced by Foxp3(+) Treg-cell transfer is sustained by splenic Tr1 cells and functionally moves from the allograft to the spleen.
authors.affiliation: San Raffaele Scientific Institute, Diabetes Research Institute, Milan, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Gagliani
authors.forename: T
authors.initials: T
authors.lastname: Jofra
authors.forename: A
authors.initials: A
authors.lastname: Valle
authors.forename: A
authors.initials: A
authors.lastname: Stabilini
authors.forename: C
authors.initials: C
authors.lastname: Morsiani
authors.forename: S
authors.initials: S
authors.lastname: Gregori
authors.forename: S
authors.initials: S
authors.lastname: Deng
authors.forename: D M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: M
authors.initials: M
authors.lastname: Atkinson
authors.forename: M
authors.initials: M
authors.lastname: Kamanaka
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: M G
authors.initials: MG
authors.lastname: Roncarolo
authors.forename: M
authors.initials: M
authors.lastname: Battaglia
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006085:Graft Survival; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D017493:Leukocyte Common Antigens
keywords: Graft; T regulatory cells; spleen; transplant tolerance