Lack of the protein tyrosine phosphatase PTPN22 strengthens transplant tolerance to pancreatic islets in mice.
OBJECTIVE
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
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.
Division of Immunology Transplantation and Infectious Diseases, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy, fousteri.georgia@hsr.it.
Georgia
G
Fousteri
Tatiana
T
Jofra
Roberta
R
Di Fonte
Nicola
N
Gagliani
Cristina
C
Morsiani
Angela
A
Stabilini
Manuela
M
Battaglia
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D001786:Blood Glucose / Q000032:analysis; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics* / Q000502:physiology*; D012307:Risk Factors; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology; D023001:Transplantation Tolerance / Q000276:immunology*
D001786:Blood Glucose; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse