Romagnani Chiara, Juelke Kerstin, Falco Michela, Morandi Barbara, D'Agostino Antonella, Costa Roberta, Ratto Giovanni, Forte Giuseppe, Carrega Paolo, Lui Gabrielle, Conte Romana, Strowig Till, Moretta Alessandro, Münz Christian, Thiel Andreas, Moretta Lorenzo, Ferlazzo Guido
Department of Clinical Immunology, German Rheumatism Research Centre, Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany.
J Immunol. 2007 Apr 15;178(8):4947-55. doi: 10.4049/jimmunol.178.8.4947.
Human NK cells can be divided into CD56(dim)CD16(+) killer Ig-like receptors (KIR)(+/-) and CD56(bright)CD16(-) KIR(-) subsets that have been characterized extensively regarding their different functions, phenotype, and tissue localization. Nonetheless, the developmental relationship between these two NK cell subsets remains controversial. We report that, upon cytokine activation, peripheral blood (PB)-CD56(bright) NK cells mainly gain the signature of CD56(dim) NK cells. Remarkably, KIR can be induced not only on CD56(bright), but also on CD56(dim) KIR(-) NK cells, and their expression correlates with lower proliferative response. In addition, we demonstrate for the first time that PB-CD56(dim) display shorter telomeres than PB- and lymph node (LN)-derived CD56(bright) NK cells. Along this line, although human NK cells collected from nonreactive LN display almost no KIR and CD16 expression, NK cells derived from highly reactive LN, efferent lymph, and PB express significant amounts of KIR and CD16, implying that CD56(bright) NK cells could acquire these molecules in the LN during inflammation and then circulate through the efferent lymph into PB as KIR(+)CD16(+) NK cells. Altogether, our results suggest that CD56(bright)CD16(-) KIR(-) and CD56(dim)CD16(+)KIR(+/-) NK cells correspond to sequential steps of differentiation and support the hypothesis that secondary lymphoid organs can be sites of NK cell final maturation and self-tolerance acquisition during immune reaction.
人类自然杀伤（NK）细胞可分为CD56（dim）CD16（+）杀伤性免疫球蛋白样受体（KIR）（+/-）和CD56（bright）CD16（-）KIR（-）亚群，关于它们不同的功能、表型和组织定位已进行了广泛的研究。尽管如此，这两个NK细胞亚群之间的发育关系仍存在争议。我们报告称，在细胞因子激活后，外周血（PB）-CD56（bright）NK细胞主要获得CD56（dim）NK细胞的特征。值得注意的是，KIR不仅可在CD56（bright）细胞上诱导表达，也可在CD56（dim）KIR（-）NK细胞上诱导表达，其表达与较低的增殖反应相关。此外，我们首次证明，PB-CD56（dim）NK细胞的端粒比PB来源和淋巴结（LN）来源的CD56（bright）NK细胞短。同样，尽管从无反应性LN收集的人类NK细胞几乎不表达KIR和CD16，但来自高反应性LN、输出淋巴和PB的NK细胞表达大量的KIR和CD16，这意味着CD56（bright）NK细胞可能在炎症期间在LN中获得这些分子，然后作为KIR（+）CD16（+）NK细胞通过输出淋巴循环进入PB。总之，我们的结果表明，CD56（bright）CD16（-）KIR（-）和CD56（dim）CD16（+）KIR（+/-）NK细胞对应于分化的连续步骤，并支持以下假设：二级淋巴器官可能是免疫反应期间NK细胞最终成熟和获得自身耐受性的场所。
