Natural killer (NK) cells are innate effector cells with critical roles not only in tumor immunosurveillance and viral immunity, but also in bacterial and fungal infections. Toll‐like receptor 2 (TLR2) can be important in the early and sustained immune responses to pathogens and tumors through the induction of cytokines and chemokines that recruit and activate immune effector cells. We investigated the role of TLR2 activation in NK cell recruitment with a view to informing approaches to induce or regulate peritoneal NK cell responses therapeutically. Peritoneal injection of TLR2 activators, including peptidoglycan and the lipopeptides FSL‐1 and Pam₃CSK₄, resulted in NK cell recruitment after 16 h with increased NK cell numbers maintained for 48 h. TLR2 activators induced large amounts of CCR2 ligands, but much smaller amounts of CCR5 and CXCR3 ligands. Consistent with this observation, NK cell migration was abrogated in CCR2‐deficient mice after peritoneal FSL‐1 injection. Adoptive transfer of CCR2‐deficient NK cells prior to peritoneal FSL‐1 activation confirmed a cell‐intrinsic component of CCR2‐mediated NK cell migration. TLR2 activation did not induce an activated NK cell phenotype, but significant changes included an increase in the KLRG1⁺ subset and decreased NKG2D expression. Although not activated in vivo, peritoneal NK cells could be activated by interleukin (IL)‐12 and IL‐18 ex vivo to express CD69 and interferonγ. These data demonstrate that TLR2‐mediated immune activation is a potent inducer of NK cell recruitment via a CCR2‐dependent mechanism and that NK cells recruited by this mechanism can respond to additional signals to exert effector cell functions.

中文翻译：

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Toll 样受体 2 激活诱导 CC 趋化因子受体 2 依赖性自然杀伤细胞募集到腹膜。

自然杀伤 (NK) 细胞是先天效应细胞，不仅在肿瘤免疫监视和病毒免疫中具有重要作用，而且在细菌和真菌感染中也具有重要作用。Toll 样受体 2 (TLR2) 通过诱导募集和激活免疫效应细胞的细胞因子和趋化因子，在对病原体和肿瘤的早期和持续免疫反应中发挥重要作用。我们研究了 TLR2 激活在 NK 细胞募集中的作用，以期为治疗上诱导或调节腹膜 NK 细胞反应的方法提供信息。腹膜注射 TLR2 激活剂，包括肽聚糖和脂肽 FSL-1 和 Pam ₃ CSK ₄，导致 NK 细胞在 16 小时后募集，NK 细胞数量增加并维持 48 小时。TLR2 激活剂诱导大量 CCR2 配体，但 CCR5 和 CXCR3 配体的量要少得多。与这一观察结果一致，腹腔注射 FSL-1 后，CCR2 缺陷小鼠的 NK 细胞迁移被取消。在腹膜 FSL-1 激活之前过继转移 CCR2 缺陷的 NK 细胞证实了 CCR2 介导的 NK 细胞迁移的细胞内在成分。TLR2 激活不会诱导激活的 NK 细胞表型，但显着变化包括 KLRG1 ⁺子集的增加和 NKG2D 表达的降低。虽然在体内未激活，但腹腔 NK 细胞可以被白介素 (IL)-12 和 IL-18体外激活表达 CD69 和干扰素γ。这些数据表明，TLR2 介导的免疫激活是通过 CCR2 依赖性机制募集 NK 细胞的有效诱导剂，并且通过该机制募集的 NK 细胞可以响应额外的信号以发挥效应细胞功能。