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Guillonneau C., M. Hill, F-X. Hubert, E. Chiffoleau, C. Hervé, X-L Li, M. Heslan, C. Usal, L. Tesson, S. Ménoret, A. Saoudi, B. Le Mauff, R. Josien, M. C. Cuturi and I. Anegon.

2007 | J Clin Invest. 117 :1096


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-g. Neutralization of IFN-g 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-g 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.