CD40Ig treatment results in allograft acceptance mediated by CD8+CD45RClow T cells, IFN-γ, and indoleamine 2,3-dioxygenase
Carole Guillonneau, … , Maria Cristina Cuturi, Ignacio Anegon
Carole Guillonneau, … , Maria Cristina Cuturi, Ignacio Anegon
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):1096-1106. https://doi.org/10.1172/JCI28801.
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Research Article

CD40Ig treatment results in allograft acceptance mediated by CD8+CD45RClow T cells, IFN-γ, and indoleamine 2,3-dioxygenase

Abstract

Treatment with CD40Ig results in indefinite allograft survival in a complete MHC-mismatched heart allograft model in the rat. Here we show that serial second, third, and fourth adoptive transfers of total splenocytes from CD40Ig-treated recipients into secondary recipients led to indefinite donor-specific allograft acceptance. Purification of splenocyte subpopulations from CD40Ig-treated recipients demonstrated that only the adoptively transferred CD8+CD45RClow subset resulted in donor-specific long-term survival, whereas CD8+CD45RClow T cells from naive animals did not. Accepted grafts displayed increased indoleamine 2,3-dioxygenase (IDO) expression restricted in the graft to ECs. Coculture of donor ECs with CD8+CD45RClow T cells purified from CD40Ig-treated animals resulted in donor-specific IDO expression dependent on IFN-γ. Neutralization of IFN-γ or IDO triggered acute allograft rejection in both CD40Ig-treated and adoptively transferred recipients. This study demonstrates for what we believe to be the first time that interference in CD40–CD40 ligand (CD40-CD40L) interactions induces allospecific CD8+ Tregs that maintain allograft survival. CD8+CD45RClow T cells act through IFN-γ production, which in turn induces IDO expression by graft ECs. Thus, donor alloantigen-specific CD8+ Tregs may promote local graft immune privilege through IDO expression.

Authors

Carole Guillonneau, Marcelo Hill, François-Xavier Hubert, Elise Chiffoleau, Caroline Hervé, Xian-Liang Li, Michèle Heslan, Claire Usal, Laurent Tesson, Séverine Ménoret, Abdelhadi Saoudi, Brigitte Le Mauff, Régis Josien, Maria Cristina Cuturi, Ignacio Anegon

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Figure 1

CD8+ T cells mediate transfer of transplantation tolerance after CD40Ig treatment.

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CD8+ T cells mediate transfer of transplantation tolerance after CD40Ig ...
Cells from control rats that had rejected their grafts or from CD40Ig-treated recipients were injected i.v. the day of transplantation into LEW.1A recipients that received LEW.1W heart transplants (day 0) and that were sublethally irradiated (4.5 Gy, at day –1). (A) Total splenocytes (50 × 106; n = 6) or splenocytes depleted of T cells (n = 2), CD4+ cells (n = 2), CD8+ cells (n = 4), or NK cells (n = 2) were injected. (B) Splenocytes (50 × 106; n = 6), purified T cells (n = 3), CD8+ T cells (n = 4), or CD4+ T cells (n = 2) were injected. Graft survival was assessed by abdominal palpation of cardiac beating. (C) Grafts were either untreated (n = 9; thick black line), treated with a control mAb (3G8) (n = 6, gray line), transduced with Addl324 (5 × 1010 IP; n = 9; dotted line), transduced with AdCD40Ig (n = 27, black line with open circles), or transduced with AdCD40Ig and injected with a depleting anti-CD8 mAb (OX8) (n = 12; black line with open triangles) or an anti-MHC class I mAb (OX18) (n = 3; black line with filled diamonds). A group of control animals received the control mAb (3G8) in addition to CD40Ig (n = 6; black line with open diamonds). **P < 0.01, ***P < 0.0001 versus animals injected with AdCD40Ig or AdCD40Ig and 3G8.