Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition.
Human NK cells kill resting but not activated microglia via NKG2D- and NKp46-mediated recognition.
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DOI：
10.4049/jimmunol.181.9.6170
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Münz C
中科院分区：
文献类型：
--
作者：
Lünemann A;Lünemann JD;Roberts S;Messmer B;Barreira da Silva R;Raine CS;Münz C
小胶质细胞是中枢神经系统（CNS）的常驻巨噬细胞样抗原呈递细胞。为了避免CNS内炎性过程和旁观者损伤的升级，小胶质细胞驱动的炎性反应需要被严格调节，并且在空间和时间上都受到限制。在创伤性、感染性和自身免疫介导的脑损伤后，在CNS中发现了自然杀伤（NK）细胞，但NK细胞募集的功能意义及其在脑炎症期间的作用机制尚不清楚。在这里，我们研究了人类NK细胞是否以及通过何种机制可能通过细胞毒性编辑静息和活化的人类小胶质细胞。IL-2激活的NK细胞以细胞接触依赖性方式有效地杀死静息同种异体和自体小胶质细胞。此外，它们在小胶质细胞识别后产生IFN-γ。活化的NK细胞与人小胶质细胞迅速形成突触，将穿孔素极化到细胞界面。抗体介导的NKG 2D和NKp 46（但不是DNAM-1和NKp 30）阻断剂减少了活化NK细胞对人类小胶质细胞的杀伤。通过TLR 4刺激上调MHC I类表面表达保护小胶质细胞免受NK细胞介导的细胞毒性。这些数据表明，脑浸润NK细胞可能通过消除静息小胶质细胞来限制人CNS内的先天性和适应性免疫应答。
Microglia are resident macrophage-like antigen presenting cells of the central nervous system (CNS). To avoid escalation of inflammatory processes and bystander damage within the CNS, microglia-driven inflammatory responses need to be tightly regulated and both spatially and temporally restricted. Following traumatic, infectious and autoimmune-mediated brain injury, natural killer (NK) cells have been found in the CNS, but the functional significance of NK cell recruitment and their mechanisms of action during brain inflammation are not well understood. Here, we investigated whether and by which mechanisms human NK cells might edit resting and activated human microglial cells via cytotoxicity. IL-2 activated NK cells efficiently killed both resting allogeneic and autologous microglia in a cell-contact dependent manner. In addition they produced IFN-γ upon microglia recognition. Activated NK cells rapidly formed synapses with human microglial cells, polarizing perforin to the cellular interface. Antibody-mediated NKG2D and NKp46, but not DNAM-1 and NKp30 blockade decreased killing of human microglia by activated NK cells. Up-regulation of MHC class I surface expression by TLR4 stimulation protected microglia from NK cell mediated cytotoxicity These data suggest that brain-infiltrating NK cells might restrict innate and adaptive immune responses within the human CNS via elimination of resting microglia.
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