CD40Ig treatment results in allograft acceptance mediated by CD8+CD45RClow T cells, IFN-γ, and indoleamine 2,3-dioxygenase
CD40Ig treatment results in allograft acceptance mediated by CD8+CD45RClow T cells, IFN-γ, and indoleamine 2,3-dioxygenase
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DOI：
10.1172/jci28801
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Anegon, Ignacio
中科院分区：
文献类型：
--
作者：
Guillonneau, Carole;Hill, Marcelo;Anegon, Ignacio
在大鼠MHC完全不匹配的心脏移植模型中，用CD 40 Ig治疗导致不确定的移植物存活。在这里，我们表明，连续第二，第三和第四过继转移总脾细胞从CD 40免疫球蛋白治疗的受体到二级受体导致无限期的供体特异性同种异体移植物接受。从CD 40 Ig处理的受体中纯化脾细胞亚群表明，只有过继转移的CD 8（+）CD 45 RC（低）亚群导致供体特异性长期存活，而来自幼稚动物的CD 8（+）CD 45 RC（低）T细胞则没有。接受的移植物显示吲哚胺2，3-双加氧酶（IDO）表达增加，仅限于移植到EC。供体EC与从CD 40 Ig处理的动物纯化的CD 8（+）CD 45 RC（低）T细胞的共培养导致依赖于IFN-γ的供体特异性IDO表达。IFN-γ或IDO的中和在CD 40 Ig治疗的和过继转移的受体中触发急性同种异体移植物排斥。本研究首次证实了干扰CD 40-CD 40配体（CD 40-CD 40 L）相互作用可诱导同种异体特异性CD 8（+）T细胞，维持同种异体移植物存活。CD 8（+）CD 45 RC（低）T细胞通过IFN-γ产生起作用，IFN-γ又通过移植EC诱导IDO表达。因此，供体同种异体抗原特异性CD 8（+）T淋巴细胞可通过IDO表达促进局部移植免疫赦免。
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(+)CD45RC(low) subset resulted in donor-specific long-term survival, whereas CD8(+)CD45RC(low) 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(+)CD45RC(low) T cells purified from CD40Ig-treated animals resulted in donor-specific IDO expression dependent on IFN-gamma. Neutralization of IFN-gamma 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(+)CD45RC(low) T cells act through IFN-gamma 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.