Sharkey Andrew M, Xiong Shiqiu, Kennedy Philippa R, Gardner Lucy, Farrell Lydia E, Chazara Olympe, Ivarsson Martin A, Hiby Susan E, Colucci Francesco, Moffett Ashley
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and
Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1QP, United Kingdom; and.
J Immunol. 2015 Oct 1;195(7):3026-32. doi: 10.4049/jimmunol.1501229. Epub 2015 Aug 28.
During human pregnancy, fetal trophoblast cells invade the decidua and remodel maternal spiral arteries to establish adequate nutrition during gestation. Tissue NK cells in the decidua (dNK) express inhibitory NK receptors (iNKR) that recognize allogeneic HLA-C molecules on trophoblast. Where this results in excessive dNK inhibition, the risk of pre-eclampsia or growth restriction is increased. However, the role of maternal, self-HLA-C in regulating dNK responsiveness is unknown. We investigated how the expression and function of five iNKR in dNK is influenced by maternal HLA-C. In dNK isolated from women who have HLA-C alleles that carry a C2 epitope, there is decreased expression frequency of the cognate receptor, KIR2DL1. In contrast, women with HLA-C alleles bearing a C1 epitope have increased frequency of the corresponding receptor, KIR2DL3. Maternal HLA-C had no significant effect on KIR2DL1 or KIR2DL3 in peripheral blood NK cells (pbNK). This resulted in a very different KIR repertoire for dNK capable of binding C1 or C2 epitopes compared with pbNK. We also show that, although maternal KIR2DL1 binding to C2 epitope educates dNK cells to acquire functional competence, the effects of other iNKR on dNK responsiveness are quite different from those in pbNK. This provides a basis for understanding how dNK responses to allogeneic trophoblast affect the outcome of pregnancy. Our findings suggest that the mechanisms that determine the repertoire of iNKR and the effect of self-MHC on NK education may differ in tissue NK cells compared with pbNK.
在人类妊娠期间，胎儿滋养层细胞侵入蜕膜并重塑母体螺旋动脉，以在妊娠期建立充足的营养供应。蜕膜中的组织自然杀伤细胞（dNK）表达抑制性自然杀伤受体（iNKR），这些受体可识别滋养层细胞上的同种异体HLA - C分子。当这导致dNK过度抑制时，子痫前期或生长受限的风险就会增加。然而，母体自身的HLA - C在调节dNK反应性中的作用尚不清楚。我们研究了母体HLA - C如何影响dNK中五种iNKR的表达和功能。在从携带C2表位的HLA - C等位基因女性中分离出的dNK中，同源受体KIR2DL1的表达频率降低。相反，携带C1表位的HLA - C等位基因的女性，其相应受体KIR2DL3的频率增加。母体HLA - C对外周血自然杀伤细胞（pbNK）中的KIR2DL1或KIR2DL3没有显著影响。这导致能够结合C1或C2表位的dNK与pbNK相比，具有非常不同的KIR库。我们还表明，尽管母体KIR2DL1与C2表位的结合使dNK细胞获得功能能力，但其他iNKR对dNK反应性的影响与pbNK中的影响截然不同。这为理解dNK对同种异体滋养层的反应如何影响妊娠结局提供了基础。我们的研究结果表明，与pbNK相比，决定iNKR库的机制以及自身MHC对自然杀伤细胞教育的影响在组织自然杀伤细胞中可能有所不同。
