Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (Tregs ) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (Teffs ) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-β, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2. The increase in NK cells was also accompanied by an increase in Treg cells, which is dependent on the presence of CD56bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.

中文翻译：

---

低剂量IL-2通过NKp44和NKp46诱导T细胞CD56bright NK调节。

小剂量白介素（IL）-2在患有自身免疫性疾病和炎性疾病的患者中已显示出临床益处。响应于低剂量IL-2免疫疗法，调节性T细胞（Tregs）和自然杀伤（NK）细胞均增加。调节性T细胞在自身免疫性疾病中的作用已被广泛研究；但是，NK细胞尚未得到充分研究。NK细胞的增加是否纯粹是一种表象现象或对自身免疫性疾病患者是否具有实际益处尚未得到充分报道。我们证明低剂量的IL-2会扩展原代人CD56bright NK细胞，从而通过保留循环抑制剂p21导致效应T细胞（Teffs）的接触依赖性细胞周期停滞。我们进一步证明NK细胞通过IL-2R-β做出反应，已显示出通过调节T细胞扩增对免疫力具有重要意义。此外，我们证明阻断NK受体NKp44和NKp46而不是NKp30可以消除与低剂量IL-2相关的增殖调控。NK细胞的增加还伴随着Treg细胞的增加，这取决于CD56bright NK细胞的存在。这些结果不仅提高了低剂量IL-2治疗中NK细胞的重要性，而且还确定了关键的人NK靶标，这可能为低剂量IL-2在自身免疫中的治疗机制提供进一步的见解。这取决于CD56bright NK细胞的存在。这些结果不仅提高了低剂量IL-2治疗中NK细胞的重要性，而且还确定了关键的人NK靶标，这可能为低剂量IL-2在自身免疫中的治疗机制提供进一步的见解。这取决于CD56bright NK细胞的存在。这些结果不仅提高了低剂量IL-2治疗中NK细胞的重要性，而且还鉴定了关键的人NK靶标，这可能为低剂量IL-2在自身免疫中的治疗机制提供进一步的见解。