Weinger Jason G, Plaisted Warren C, Maciejewski Sonia M, Lanier Lewis L, Walsh Craig M, Lane Thomas E
Department of Molecular Biology & Biochemistry; Sue and Bill Gross Stem Cell Center, University of California, Irvine, California, USA.
Stem Cells. 2014 Oct;32(10):2690-701. doi: 10.1002/stem.1760.
Transplantation of major histocompatibility complex-mismatched mouse neural precursor cells (NPCs) into mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in rapid rejection that is mediated, in part, by T cells. However, the contribution of the innate immune response to allograft rejection in a model of viral-induced neurological disease has not been well defined. Herein, we demonstrate that the natural killer (NK) cell-expressing-activating receptor NKG2D participates in transplanted allogeneic NPC rejection in mice persistently infected with JHMV. Cultured NPCs derived from C57BL/6 (H-2(b) ) mice express the NKG2D ligand retinoic acid early precursor transcript (RAE)-1 but expression was dramatically reduced upon differentiation into either glia or neurons. RAE-1(+) NPCs were susceptible to NK cell-mediated killing whereas RAE-1(-) cells were resistant to lysis. Transplantation of C57BL/6-derived NPCs into JHMV-infected BALB/c (H-2(d) ) mice resulted in infiltration of NKG2D(+) CD49b(+) NK cells and treatment with blocking antibody specific for NKG2D increased survival of allogeneic NPCs. Furthermore, transplantation of differentiated RAE-1(-) allogeneic NPCs into JHMV-infected BALB/c mice resulted in enhanced survival, highlighting a role for the NKG2D/RAE-1 signaling axis in allograft rejection. We also demonstrate that transplantation of allogeneic NPCs into JHMV-infected mice resulted in infection of the transplanted cells suggesting that these cells may be targets for infection. Viral infection of cultured cells increased RAE-1 expression, resulting in enhanced NK cell-mediated killing through NKG2D recognition. Collectively, these results show that in a viral-induced demyelination model, NK cells contribute to rejection of allogeneic NPCs through an NKG2D signaling pathway.
将主要组织相容性复合体不匹配的小鼠神经前体细胞（NPC）移植到持续感染嗜神经小鼠肝炎病毒（JHMV）JHM株的小鼠体内，会导致快速排斥反应，部分由T细胞介导。然而，在病毒诱导的神经疾病模型中，先天免疫反应对同种异体移植排斥反应的作用尚未明确界定。在此，我们证明表达天然杀伤（NK）细胞激活受体NKG2D参与了持续感染JHMV的小鼠中移植的异基因NPC排斥反应。源自C57BL/6（H-2(b)）小鼠的培养NPC表达NKG2D配体视黄酸早期前体转录本（RAE）-1，但在分化为神经胶质细胞或神经元后表达显著降低。RAE-1(+) NPC易受NK细胞介导的杀伤，而RAE-1(-)细胞对裂解具有抗性。将源自C57BL/6的NPC移植到感染JHMV的BALB/c（H-2(d)）小鼠中导致NKG2D(+) CD49b(+) NK细胞浸润，用针对NKG2D的阻断抗体治疗可提高异基因NPC的存活率。此外，将分化的RAE-1(-)异基因NPC移植到感染JHMV的BALB/c小鼠中可提高存活率，突出了NKG2D/RAE-1信号轴在同种异体移植排斥反应中的作用。我们还证明将异基因NPC移植到感染JHMV的小鼠中会导致移植细胞感染，表明这些细胞可能是感染靶点。培养细胞的病毒感染增加了RAE-1表达，导致通过NKG2D识别增强NK细胞介导的杀伤。总体而言，这些结果表明，在病毒诱导的脱髓鞘模型中，NK细胞通过NKG2D信号通路促进异基因NPC的排斥。
