Transplant tolerance to pancreatic islets is initiated in the graft and sustained in the spleen

N. Gagliani, T. Jofra, A. Valle, A. Stabilini, C. Morsiani, S. Gregori, S. Deng, D. M. Rothstein, M. Atkinson, M. Kamanaka, R. A. Flavell, M. G. Roncarolo, M. Battaglia

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish
Pages (from-to)1963-1975
Number of pages13
JournalAmerican Journal of Transplantation
Volume13
Issue number8
DOIs
Publication statusPublished - Aug 2013

Keywords

  • Graft
  • spleen
  • T regulatory cells
  • transplant tolerance

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

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