Kedia-Mehta Nidhi, Choi Chloe, McCrudden Aisling, Littwitz-Salomon Elisabeth, Fox Proinnsias G, Gardiner Clair M, Finlay David K
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
Immunometabolism. 2019;1:e190014. doi: 10.20900/immunometab20190014. Epub 2019 Sep 25.
Natural Killer (NK) cells are lymphocytes with an important role in anti-tumour responses. NK cells bridge the innate and adaptive arms of the immune system; they are primed for immediate anti-tumour function but can also have prolonged actions alongside the adaptive T cell response. However, the key signals and cellular processes that are required for extended NK cell responses are not fully known. Herein we show that murine NK cell interaction with tumour cells induces the expression of CD25, the high affinity IL2 receptor, rendering these NK cells highly sensitive to the T cell-derived cytokine IL2. In response to IL2, CD25 NK cells show robust increases in metabolic signalling pathways (mTORC1, cMyc), nutrient transporter expression (CD71, CD98), cellular growth and in NK cell effector functions (IFNγ, granzyme B). Specific ligation of an individual activating NK cell receptor, NK1.1, showed similar increases in CD25 expression and IL2-induced responses. NK cell receptor ligation and IL2 collaborate to induce mTORC1/cMyc signalling leading to high rates of glycolysis and oxidative phosphorylation (OXPHOS) and prolonged NK cell survival. Disrupting mTORC1 and cMyc signalling in CD25 tumour interacting NK cells prevents IL2-induced cell growth and function and compromises NK cell viability. This study reveals that tumour cell interactions and T cell-derived IL2 cooperate to promote robust and prolonged NK cell anti-tumour metabolic responses.
自然杀伤（NK）细胞是淋巴细胞，在抗肿瘤反应中发挥重要作用。NK细胞连接免疫系统的固有免疫和适应性免疫分支；它们已做好准备立即发挥抗肿瘤功能，但也可在适应性T细胞反应的同时产生持久作用。然而，NK细胞延长反应所需的关键信号和细胞过程尚不完全清楚。在此我们表明，小鼠NK细胞与肿瘤细胞的相互作用诱导了高亲和力白细胞介素2受体CD25的表达，使这些NK细胞对T细胞来源的细胞因子白细胞介素2高度敏感。响应白细胞介素2，CD25阳性NK细胞在代谢信号通路（mTORC1、cMyc）、营养转运蛋白表达（CD71、CD98）、细胞生长以及NK细胞效应功能（干扰素γ、颗粒酶B）方面均有显著增加。单个激活型NK细胞受体NK1.1的特异性连接显示CD25表达和白细胞介素2诱导的反应有类似增加。NK细胞受体连接和白细胞介素2协同诱导mTORC1/cMyc信号传导，导致高糖酵解和氧化磷酸化（OXPHOS）速率以及NK细胞的长期存活。破坏CD25阳性肿瘤相互作用NK细胞中的mTORC1和cMyc信号传导可阻止白细胞介素2诱导的细胞生长和功能，并损害NK细胞活力。这项研究表明，肿瘤细胞相互作用和T细胞来源的白细胞介素2协同促进强大而持久的NK细胞抗肿瘤代谢反应。
