Role of IFNgamma in allograft tolerance mediated by CD4+CD25+ regulatory T cells by induction of IDO in endothelial cells.
Regulatory T cells have been described to specifically accumulate at the site of regulation together with effector T cells and antigen-presenting cells, establishing a state of local immune privilege. However the mechanisms of this interplay remain to be defined. We previously demonstrated, in a fully MHC mismatched rat cardiac allograft combination, that a short-term treatment with a deoxyspergualine analogue, LF15-0195, induces long-term allograft tolerance with a specific expansion of regulatory CD4+CD25+T cells that accumulate within the graft. In this study, we show that following transfer of regulatory CD4+T cells to a secondary irradiated recipient, regulatory CD25+Foxp3+ and CD25+Foxp3(-) CD4+T cells accumulate at the graft site and induce graft endothelial cell expression of Indoleamine 2, 3-dioxygenase (IDO) by an IFNgamma-dependent mechanism. Moreover, in vivo transfer of tolerance can be abrogated by blocking IFNgamma or IDO, and anti-IFNgamma reduces the survival/expansion of alloantigen-induced regulatory Foxp3+CD4+T cells. Together, our results demonstrate interrelated mechanisms between regulatory CD4+CD25+T cells and the graft endothelial cells in this local immune privilege, and a key role for IFNgamma and IDO in this process.
Thebault
P
P
INSERM, U643, Nantes, F44000 France.
Condamine
T
T
Heslan
M
M
Hill
M
M
Bernard
I
I
Saoudi
A
A
Josien
R
R
Anegon
I
I
Cuturi
M C
MC
Chiffoleau
E
E
D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology; D004790:Enzyme Induction; D051858:Forkhead Transcription Factors / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*
D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D006146:Guanidines; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; C434185:LF 150195; D007371:Interferon-gamma