Regulation of Natural Killer Cells by TGF-beta

描述(申请人提供)：自然杀伤(NK)细胞对宿主控制病毒感染和肿瘤形成至关重要，并可被促炎症细胞因子如白介素12、白介素18和I型干扰素快速激活。最近，IL-12和STAT4信号也被证明是产生病毒特异性NK细胞记忆所必需的。这些激活的细胞因子被认为被抑制的细胞因子抵消，以调节效应器的反应，防止附带损害。然而，抑制性细胞因子，如转化生长因子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。了解转化生长因子在抑制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，本研究将探讨免疫抑制细胞因子转化生长因子在NK细胞功能中的作用，特别是在针对病毒感染和肿瘤的效应和记忆反应的产生中。我们将携带转化生长因子受体II等位基因的小鼠与插入NKp46基因座(Nkp46iCre)的改良Cre重组酶(ICre)的小鼠杂交，产生了含有转化生长因子不敏感的NK细胞的小鼠。我们将直接比较这些小鼠的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环境中的NK细胞表型。对于病毒研究，我们将使用我们实验室建立的小鼠巨细胞病毒(MCMV)感染模型。这是一个特别重要的模型，因为人类巨细胞病毒(HCMV)会在免疫抑制患者(如接受化疗或骨髓移植的患者)中导致危及生命的并发症。对于肿瘤研究，我们将使用B16黑色素瘤模型，众所周知，这种黑色素瘤容易受到NK细胞溶解的影响。通过这项研究，我们希望阐明转化生长因子在调节NK细胞效应器反应中的作用，以及如何潜在地操纵这一作用来提高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.