Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells:: relevance to mechanism of heart allograft tolerance
Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells:: relevance to mechanism of heart allograft tolerance
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DOI：
10.4049/jimmunol.179.10.6749
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Burlingham, William J.
中科院分区：
文献类型：
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作者：
Molitor-Dart, Melanie L.;Andrassy, Joachim;Burlingham, William J.
我们假设发育暴露于非遗传性母体Ags （NIMA）会导致异体抗原特异性的自然和适应性T调节（T- r）细胞。我们比较了暴露于母体H-2(d) （NIMA(d)）的后代与未暴露的对照组。体外试验未发现移植前T细胞反应有任何差异。过继性转移实验显示，与对照脾细胞相比，NIMA(d)暴露的CD4(+) T细胞的淋巴细胞增殖更低，细胞表面tgf - β表达更高。NIMA(d)暴露的脾细胞表现出破伤风特异性延迟型超敏反应的旁观者抑制，这与抗体对tgf - β和IL-10的抑制是相反的。同种异体T效应细胞在B6D2F1脾细胞或DBA/2心脏移植后均被诱导，但在NIMA(d)暴露小鼠中，不同程度地受到TR细胞的控制。一些（40%）暴露于NIMA(d)的小鼠接受了DBA/2同种异体移植物，而另一些（60%）则延迟排斥。与对照组相比，NIMA(d)暴露小鼠的T效应反应降低，脾脏和淋巴结中的Foxp3(+) TR细胞(CD4(+)CD25（+)Foxp3(+) T- r）增加。NIMA（d)暴露受体区别于所有其他小鼠的关键特征是：1)在淋巴结和异体移植物中的CD4（+)CD25(+) T细胞亚群中产生IL-10和tgf - β细胞的频率更高，2）对B6D2F1 Ags的延迟型超敏反应受到抑制，3）异体移植物中富集了LAP(+), Foxp3（+）和CD4(+) T细胞，CD8(+) T细胞很少。我们得出结论，有益的NIMA效应是由于在个体发育过程中诱导了NIMA特异性的TR细胞。它们在成虫体内的持久性，以及宿主将它们动员到移植物上的能力，可能决定了是否实现了nima特异性耐受。
We hypothesize that developmental exposure to noninherited maternal Ags (NIMA) results in alloantigen-specific natural and adaptive T regulatory (T-R) cells. We compared offspring exposed to maternal H-2(d) (NIMA(d)) with nonexposed controls. In vitro assays did not reveal any differences in T cell responses pretransplant. Adoptive transfer assays revealed lower lymphoproliferation and greater cell surface TGF-beta expression on CD4(+) T cells of NIMA(d)-exposed vs control splenocytes. NIMA(d)-exposed splenocytes exhibited bystander suppression of tetanus-specific delayed-type hypersensitivity responses, which was reversed with Abs to TGF-beta and IL-10. Allospecific T effector cells were induced in all mice upon i.v. challenge with B6D2F1 splenocytes or a DBA/2 heart transplant, but were controlled in NIMA(d)-exposed mice by TR cells to varying degrees. Some (40%) NIMA(d)-exposed mice accepted a DBA/2 allograft while others (60%) rejected in delayed fashion. Rejector and acceptor NIMA(d)-exposed mice had reduced T effector responses and increased Foxp3(+) TR cells (CD4(+)CD25(+)Foxp3(+) T-R) in Spleen and lymph nodes compared with controls. The key features distinguishing NIMA(d)-exposed acceptors from all other mice were: 1) higher frequency of IL-10- and TGF-beta-producing cells primarily in the CD4(+)CD25(+) T cell subset within lymph nodes and allografts, 2) a suppressed delayed-type hypersensitivity response to B6D2F1 Ags, and 3) allografts enriched in LAP(+), Foxp3(+), and CD4(+) T cells, with few CD8(+) T cells. We conclude that the beneficial NIMA effect is due to induction of NIMA-specific TR cells during ontogeny. Their persistence in the adult, and the ability of the host to mobilize them to the graft, may determine whether NIMA-specific tolerance is achieved.