Transplant Tolerance to Pancreatic Islets Is Initiated in the Graft and Sustained in the Spleen

• Published in: American journal of transplantation Vol. 13; no. 8; pp. 1963 - 1975
• Main Authors: Gagliani, N., Jofra, T., Valle, A., Stabilini, A., Morsiani, C., Gregori, S., Deng, S., Rothstein, D. M., Atkinson, M., Kamanaka, M., Flavell, R. A., Roncarolo, M. G., Battaglia, M.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley 01-08-2013; Elsevier Limited
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - immunology; Biological and medical sciences; Bone marrow; 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; Graft Survival; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation; Leukocyte Common Antigens - immunology; Leukocyte Common Antigens - metabolism; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Spleen; Spleen - immunology; Spleen - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T regulatory cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; transplant tolerance; Transplantation Tolerance - immunology; Transplantation, Homologous; Transplants & implants; Spleen; T regulatory cell; Treatment; T regulatory cells; Surgery; Immune tolerance; Langerhans islet; Graft; Transplantation; transplant tolerance; Endocrine pancreas; spleen
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/ajt.12333

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.
In a model of allogeneic pancreatic islet transplantation, Foxp3+ Treg cells exert their regulatory function within the allograft and initiate engraftment locally and in a non‐antigen‐specific manner, whereas CD4+CD25‐ T cells, which contain IL‐10‐producing Tr1 cells, act from the spleen and are key to the maintenance of long‐term tolerance. See editorial by Gill on page 1945.