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1.
Clin Exp Immunol ; 201(2): 222-230, 2020 08.
Article in English | MEDLINE | ID: mdl-32293025

ABSTRACT

T regulatory type 1 (Tr1) cells are a class of regulatory T cells (Tregs ) participating in peripheral tolerance, hence the rationale behind their testing in clinical trials in different disease settings. One of their applications is tolerance induction to allogeneic islets for long-term diabetes-free survival. Currently the cellular and molecular mechanisms that promote Tr1-cell induction in vivo remain poorly understood. We employed a mouse model of transplant tolerance where treatment with granulocyte colony-stimulating factor (G-CSF)/rapamycin induces permanent engraftment of allogeneic pancreatic islets in C57BL/6 mice via Tr1 cells. The innate composition of graft and spleen cells in tolerant mice was analyzed by flow cytometry. Graft phagocytic cells were co-cultured with CD4+ T cells in vitro to test their ability to induce Tr1-cell induction. Graft phagocytic cells were depleted in vivo at different time-points during G-CSF/rapamycin treatment, to identify their role in Tr1-cell induction and consequently in graft survival. In the spleen, the site of Tr1-cell induction, no differences in the frequencies of macrophages or dendritic cells (DC) were observed. In the graft, the site of antigen uptake, a high proportion of macrophages and not DC was detected in tolerant but not in rejecting mice. Graft-infiltrating macrophages of G-CSF/rapamycin-treated mice had an M2 phenotype, characterized by higher CD206 expression and interleukin (IL)-10 production, whereas splenic macrophages only had an increased CD206 expression. Graft-infiltrating cells from G-CSF/rapamycin-treated mice-induced Tr1-cell expansion in vitro. Furthermore, Tr1-cell induction was perturbed upon in-vivo depletion of phagocytic cells, early and not late during treatment, leading to graft loss suggesting that macrophages play a key role in tolerance induction mediated by Tr1 cells. Taken together, in this mouse model of Tr1-cell induced tolerance to allogeneic islets, M2 macrophages infiltrating the graft upon G-CSF/rapamycin treatment are key for Tr1-cell induction. This work provides mechanistic insight into pharmacologically induced Tr1-cell expansion in vivo in this stringent model of allogeneic transplantation.


Subject(s)
Diabetes Mellitus, Experimental/immunology , Insulin-Secreting Cells/cytology , Islets of Langerhans Transplantation , Macrophages/immunology , T-Lymphocytes, Regulatory/immunology , Th1 Cells/immunology , Animals , Cells, Cultured , Disease Models, Animal , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Insulin-Secreting Cells/transplantation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Sirolimus/metabolism , Transplantation Tolerance , Transplantation, Homologous
2.
Am J Transplant ; 13(8): 1963-75, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23834659

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.


Subject(s)
Islets of Langerhans Transplantation , Islets of Langerhans/immunology , Spleen/immunology , T-Lymphocytes, Regulatory/immunology , Transplantation Tolerance/immunology , Adoptive Transfer , Animals , Antibodies, Monoclonal/immunology , CD4 Antigens/immunology , CD4 Antigens/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/metabolism , Graft Survival , Islets of Langerhans/metabolism , Leukocyte Common Antigens/immunology , Leukocyte Common Antigens/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Spleen/metabolism , T-Lymphocytes, Regulatory/metabolism , Transplantation, Homologous
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