Bunting Mark D, Vyas Maulik, Requesens Marta, Langenbucher Adam, Schiferle Erik B, Manguso Robert T, Lawrence Michael S, Demehri Shadmehr
Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Sci Adv. 2022 Mar 18;8(11):eabk3327. doi: 10.1126/sciadv.abk3327. Epub 2022 Mar 16.
Natural killer (NK) cells reject major histocompatibility complex class I (MHC-I)-deficient bone marrow through direct cytotoxicity but not solid organ transplants devoid of MHC-I. Here, we demonstrate an immediate switch in NK cell function upon exit from the circulation, characterized by a shift from direct cytotoxicity to chemokine/cytokine production. In the skin transplant paradigm, combining an NK cell-specific activating ligand, m157, with missing self MHC-I resulted in complete graft rejection, which was dependent on NK cells as potential helpers and T cells as effectors. Extracellular matrix proteins, collagen I, collagen III, and elastin, blocked NK cell cytotoxicity and promoted their chemokine/cytokine production. NK cell cytotoxicity against MHC-I-deficient melanoma in the skin was markedly increased by blocking tumor collagen deposition. MHC-I down-regulation occurred in solid human cancers but not leukemias, which could be directly targeted by circulating cytotoxic NK cells. Our findings uncover a fundamental mechanism that restricts direct NK cell cytotoxicity in peripheral tissues.
自然杀伤（NK）细胞通过直接细胞毒性作用排斥主要组织相容性复合体I类（MHC-I）缺陷的骨髓，但不会排斥缺乏MHC-I的实体器官移植。在此，我们证明了NK细胞离开循环系统后功能会立即发生转变，其特征是从直接细胞毒性作用转变为趋化因子/细胞因子产生。在皮肤移植模型中，将NK细胞特异性激活配体m157与缺失的自身MHC-I相结合，导致完全的移植物排斥反应，这依赖于作为潜在辅助细胞的NK细胞和作为效应细胞的T细胞。细胞外基质蛋白，即I型胶原蛋白、III型胶原蛋白和弹性蛋白，可阻断NK细胞的细胞毒性作用并促进其趋化因子/细胞因子产生。通过阻断肿瘤胶原蛋白沉积，可显著增强皮肤中NK细胞对MHC-I缺陷黑色素瘤的细胞毒性作用。MHC-I下调发生在人类实体癌而非白血病中，循环中的细胞毒性NK细胞可直接靶向白血病。我们的研究结果揭示了一种限制外周组织中NK细胞直接细胞毒性作用的基本机制。
