Regulation of Natural Killer Cells by TGF-beta

描述（由申请方提供）：自然杀伤（NK）细胞对于宿主控制病毒感染和肿瘤发生至关重要，并可被促炎细胞因子（如白介素（IL）-12、IL-18和I型干扰素）快速激活。IL-12和STAT 4信号传导最近也被证明是产生病毒特异性NK细胞记忆所必需的。这些激活性细胞因子被认为通过抑制性细胞因子来平衡，以调节效应子应答并防止附带损伤。然而，抑制性细胞因子，如转化生长因子（TGF）-β，在病毒感染或肿瘤发生过程中控制NK细胞反应的确切作用尚不清楚。了解TGF-β在抑制NK细胞介导的对肿瘤和病毒的免疫应答中的作用对于释放NK细胞在未来免疫治疗中的全部潜力至关重要。为此，本研究将研究免疫抑制细胞因子TGF-β在NK细胞功能中的作用，特别是在产生针对病毒感染和肿瘤的效应和记忆应答中的作用。我们通过将携带floxed TGF-β受体II等位基因（TGF-β RIIfl/fl）的小鼠与具有插入NKp 46基因座的改进的Cre重组酶（iCre）的小鼠（Nkp 46 iCre）杂交，产生了含有TGF-β不敏感NK细胞的小鼠。我们将比较这些小鼠的NK细胞表型与野生型对照的NK细胞表型，以及在骨髓嵌合体和过继转移设置。对于病毒研究，我们将使用在我们实验室建立良好的小鼠巨细胞病毒（MCMV）感染模型。这是一个特别重要的模型，因为人巨细胞病毒（HCMV）会在免疫抑制患者（如接受化疗或骨髓移植的患者）中引起危及生命的并发症。对于肿瘤研究，我们将使用B16黑色素瘤模型，已知该模型对NK细胞裂解敏感。通过这项研究，我们希望阐明TGF-β在调节NK细胞效应反应中的作用，以及如何潜在地操纵这种作用以改善NK细胞介导的免疫。

DESCRIPTION (provided by applicant): Natural killer (NK) cells are critical for host control of viral infections and tumorigenesis and are rapidly activated by pro-inflammatory cytokines such as interleukin (IL)-12, IL-18, and type I interferons. IL-12 and STAT4 signaling have also recently been shown to be required for the generation of virus-specific NK cell memory. These activating cytokines are thought to be counter-balanced by suppressive cytokines in order to regulate the effector response and prevent collateral damage. However, the exact role of suppressive cytokines, such as transforming growth factor (TGF)-ß, in controlling NK cell responses during viral infection or tumorigenesis is not yet known. Understanding the role of TGF-ß in suppressing the NK cell mediated immune response to tumor and virus will be critical in unleashing NK cells' full potential in future immunotherapies. To that end, this study will investigate the role of the immunosuppressive cytokine TGF-ß in NK cell function, particularly in the generation of effector and memory responses against viral infections and tumors. We have generated mice containing TGF-ß-insensitive NK cells by crossing mice carrying floxed TGF-ß receptor II alleles (TGF-ßRIIfl/fl) to mice with the improved Cre-recombinase (iCre) inserted into the NKp46 gene locus (Nkp46iCre). We will compare the NK cell phenotype of these mice to that of wild-type controls directly, as well as in the bone marrow chimera and adoptive transfer settings. For viral studies, we will use the mouse cytomegalovirus (MCMV) infection model that is well established in our lab. This is a particularly important model because human cytomegalovirus (HCMV) causes life-threatening complications in immunosuppressed patients such as those undergoing chemotherapy or bone marrow transplantation. For tumor studies, we will use the B16 melanoma model, which is known to be susceptible to NK cell lysis. Through this investigation we hope to elucidate the role of TGF-ß in regulating the NK cell effector response and how this role could potentially be manipulated to improve NK cell mediated immunity.