Erlebacher Adrian, Vencato Daniela, Price Kelly A, Zhang Dorothy, Glimcher Laurie H
Department of Pathology, Experimental Pathology Program, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
J Clin Invest. 2007 May;117(5):1399-411. doi: 10.1172/JCI28214. Epub 2007 Apr 19.
How the fetus escapes rejection by the maternal immune system remains one of the major unsolved questions in transplantation immunology. Using a system to visualize both CD4+ and CD8+ T cell responses during pregnancy in mice, we find that maternal T cells become aware of the fetal allograft exclusively through "indirect" antigen presentation, meaning that T cell engagement requires the uptake and processing of fetal/placental antigen by maternal APCs. This reliance on a relatively minor allorecognition pathway removes a major threat to fetal survival, since it avoids engaging the large number of T cells that typically drive acute transplant rejection through their ability to directly interact with foreign MHC molecules. Furthermore, CD8+ T cells that indirectly recognize fetal/placental antigen undergo clonal deletion without priming for cytotoxic effector function and cannot induce antigen-specific fetal demise even when artificially activated. Antigen presentation commenced only at mid-gestation, in association with the endovascular invasion of placental trophoblasts and the hematogenous release of placental debris. Our results suggest that limited pathways of antigen presentation, in conjunction with tandem mechanisms of immune evasion, contribute to the unique immunological status of the fetus. The pronounced degree of T cell ignorance of the fetus also has implications for the pathophysiology of immune-mediated early pregnancy loss.
胎儿如何逃过母体免疫系统的排斥，仍是移植免疫学中一个主要的未解问题。利用一个系统来观察小鼠孕期CD4+和CD8+ T细胞的反应，我们发现母体T细胞仅通过“间接”抗原呈递来识别胎儿同种异体移植物，这意味着T细胞的激活需要母体抗原呈递细胞摄取并处理胎儿/胎盘抗原。对相对次要的同种异体识别途径的这种依赖消除了对胎儿存活的一个主要威胁，因为它避免了激活大量通常通过直接与外来MHC分子相互作用而引发急性移植排斥反应的T细胞。此外，间接识别胎儿/胎盘抗原的CD8+ T细胞会发生克隆清除，不会被启动发挥细胞毒性效应功能，即使人工激活也不能诱导抗原特异性的胎儿死亡。抗原呈递仅在妊娠中期开始，与胎盘滋养层细胞的血管内侵入以及胎盘碎片的血源性释放有关。我们的结果表明，有限的抗原呈递途径，与串联的免疫逃避机制共同作用，促成了胎儿独特的免疫状态。T细胞对胎儿明显的忽视程度，也对免疫介导的早期妊娠丢失的病理生理学有影响。
