Lack of the protein tyrosine phosphatase PTPN22 strengthens transplant tolerance to pancreatic islets in mice

Georgia Fousteri, Tatiana Jofra, Roberta Di Fonte, Nicola Gagliani, Cristina Morsiani, Angela Stabilini, Manuela Battaglia

Research output: Contribution to journalArticle

Abstract

Aims/hypothesis: Protein tyrosine phosphatase non-receptor 22 (PTPN22) plays a central role in T cell, B cell and innate immune cell signalling. A genetic variation in Ptpn22 is considered a major risk factor for the development of type 1 diabetes and has been the subject of extensive study. While several reports have addressed how Ptpn22 might predispose to autoimmunity, its involvement in other immune-mediated diseases, such as allograft rejection, has not been explored. Methods: To address a possible function for Ptpn22 in allograft rejection, we used a mouse model of pancreatic islet transplantation. We performed transplant tolerance experiments and determined how PTPN22 shapes tolerance induction and maintenance. Results: Ptpn22−/− recipient mice generate higher numbers of alloreactive T cells after allogeneic pancreatic islet transplantation compared with wild-type (WT) mice, but reject grafts with similar kinetics. This is not only due to their well-documented increase in forkhead box protein P3 (FOXP3)+ T regulatory (Treg) cells but also to the expansion of T regulatory type 1 (Tr1) cells caused by the lack of PTPN22. In addition, a tolerogenic treatment known to induce transplant tolerance in WT mice via Tr1 cell generation is more effective in Ptpn22−/− mice as a consequence of boosting both Tr1 and FOXP3+ Treg cells. Conclusions/interpretation: A lack of PTPN22 strengthens transplant tolerance to pancreatic islets by expanding both FOXP3+ Treg and Tr1 cells. These data suggest that targeting PTPN22 could serve to boost transplant tolerance.

Original languageEnglish
Pages (from-to)1319-1328
Number of pages10
JournalDiabetologia
Volume58
Issue number6
DOIs
Publication statusPublished - Jun 1 2015

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Keywords

  • Alloreactivity
  • FOXP3
  • G-CSF
  • Pancreatic islet transplantation
  • PTPN22
  • Rapamycin
  • Tr1 cells
  • Transplant tolerance
  • Treg cells

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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