KIR in adaptive immunity: in vivo relevance for human disease

适应性免疫中的 KIR：与人类疾病的体内相关性

• 批准号: MR/J007439/1
• 负责人: Becca Asquith
• 金额: $ 46.01万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ007439%2F1
• 关键词: KIR; adaptive; immunity; vivo; relevance

BACKGROUNDThis project capitalises on our recent work on killer cell immunoglobulin-like receptors (KIRs). KIRs are expressed predominantly on natural killer cells where they play an important role in innate immunity. There are few studies elucidating the impact of KIRs on the T cell response in human disease.WORK WHICH HAS LED UP TO THIS PROJECT Our research has revealed a novel and unexpected way in which immunity can be enhanced. We have found that a particular KIR (KIR2DL2) enhances both protective and detrimental HLA class I disease associations in two chronic virus infections (hepatitis C virus and human T lymphotropic virus) and is an important determinant of clinical outcome. Strikingly, although KIRs are primarily associated with innate immunity, we believe our observations suggest that they also have a major impact on the adaptive immune response. A NEW ROLE FOR KIR? Many associations between disease outcome and pairs of KIR-HLA genes have been reported. In every case the KIR-HLA pair consisted of a KIR and the HLA molecule that it binds and the effect was attributed to direct NK killing; i.e. NK cells express the KIR which binds its HLA ligand, this modulates the NK killing of virus-infected cells and thus affects disease outcome. What we have observed is quite different. We report that associations between HLA class I molecules and disease outcome are weak in the absence of KIR2DL2 but are enhanced in the presence of KIRDL2, more so if there are two copies of the KIR2DL2 gene. This is true for multiple HLA-A, B and C alleles, most of which do not bind KIR2DL2. We see this effect for two different virus infections and for both protective and detrimental HLA associations. Both clinical outcome and, independently, viral burden are affected. Additionally, the protective effect of HLA binding of many different viral peptides is also enhanced by KIR2DL2. In contrast KIR2DL2 with its C1 ligand (not in the context of protective or detrimental HLA molecules) has absolutely no detectable impact on any measure for either virus. We think that this KIR2DL2-enhancement of HLA class I associations cannot be explained by NK killing of virus-infected cells. Instead we postulate a novel interaction between KIRs and adaptive immunity that is having a significant impact on clinical outcome.HYPOTHESIS We suggest KIR2DL2 enhances adaptive immunity by increasing T cell survival during chronic infection and thus enhances the strength of the CD8+ T cell response. If the CD8+ T cell is restricted by a protective HLA class I molecule then, in a KIR2DL2+ person, the CD8+ T cell response will be stronger and protective associations will be enhanced, but equally if CD8+ T cells are restricted by a detrimental HLA molecule then the detrimental associations will be enhanced. OBJECTIVESWe will test the hypothesis that KIR2DL2 enhances adaptive immunity and investigate how general this effect is. Specifically, we will test if the CD8+ T cell response to hepatitis C virus and human T lymphotropic virus is stronger in individuals with KIR2DL2 and we will investigate if KIR2DL2 also impacts on the risk of developing virus-associated leukemia.IMPORTANCEOur data are consistent with an unexpected and clinically important interaction between innate and adaptive immunity. Understanding how the CD8+ T cell response can be enhanced would represent a significant advance in our basic knowledge and would be a major step towards combating the dysfunctions associated with weakened immunity. APPROACH We take a multidisciplinary systems approach in which we combine mathematical modelling and sequencing of the host and pathogen genomes with more "traditional" cellular immunology. Investigating the human immune response is challenging; by using this combined approach we gain unique insight.

该项目利用了我们最近在杀伤细胞免疫球蛋白样受体（KIR）方面的工作。KIR主要在自然杀伤细胞上表达，在天然免疫中发挥重要作用。有几个研究阐明了在人类疾病中KIR对T细胞反应的影响。导致这个项目的工作我们的研究揭示了一种新的和意想不到的方式，可以增强免疫力。我们已经发现，一个特定的KIR（KIR 2DL 2）增强保护性和有害的HLA I类疾病协会在两个慢性病毒感染（丙型肝炎病毒和人类T淋巴细胞病毒），是一个重要的决定因素的临床结果。引人注目的是，尽管KIR主要与先天免疫相关，但我们相信我们的观察表明它们对适应性免疫反应也有重大影响。KIR的新角色？疾病结果与KIR-HLA基因对之间的许多关联已被报道。在每种情况下，KIR-HLA对由KIR和它结合的HLA分子组成，并且该作用归因于直接NK杀伤;即NK细胞表达结合其HLA配体的KIR，这调节病毒感染细胞的NK杀伤，从而影响疾病结果。我们所观察到的是完全不同的。我们报告说，HLA I类分子和疾病的结果之间的关联是弱的KIR 2DL 2的情况下，但增强KIR 2DL 2的存在下，更是如此，如果有两个拷贝的KIR 2DL 2基因。这对于多个HLA-A、B和C等位基因是正确的，其中大多数不结合KIR 2DL 2。我们在两种不同的病毒感染以及保护性和有害的HLA关联中都看到了这种效应。临床结果和独立的病毒负荷都受到影响。此外，许多不同病毒肽的HLA结合的保护作用也被KIR 2DL 2增强。相反，KIR 2DL 2及其C1配体（不在保护性或有害HLA分子的背景下）对任一病毒的任何测量都绝对没有可检测的影响。我们认为这种KIR 2DL 2增强HLA I类相关性不能用NK杀伤病毒感染细胞来解释。相反，我们假设KIR和适应性免疫之间的一种新的相互作用，这对临床outcome.Hypothesis有显著的影响，我们认为KIR 2DL 2通过增加慢性感染期间的T细胞存活来增强适应性免疫，从而增强CD 8 + T细胞应答的强度。如果CD 8 + T细胞受到保护性HLA I类分子的限制，那么在KIR 2DL 2+人中，CD 8 + T细胞应答将更强，保护性关联将增强，但同样地，如果CD 8 + T细胞受到有害HLA分子的限制，那么有害关联将增强。我们将检验KIR 2DL 2增强适应性免疫的假设，并研究这种效应的普遍性。具体来说，我们将测试是否CD 8 + T细胞对丙型肝炎病毒和人类T淋巴细胞病毒的反应是更强的个人与KIR 2DL 2，我们将调查，如果KIR 2DL 2也影响发展病毒相关leukemia.IMPORTANCEOur数据的风险是一致的先天性和适应性免疫之间的意想不到的和临床上重要的相互作用。了解如何增强CD 8 + T细胞反应将代表我们基础知识的重大进步，并将是对抗与免疫力减弱相关的功能障碍的重要一步。方法我们采用多学科系统方法，将宿主和病原体基因组的联合收割机数学建模和测序与更“传统”的细胞免疫学相结合。研究人类免疫反应具有挑战性;通过使用这种组合方法，我们获得了独特的见解。

项目成果

BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data.

• DOI: 10.1371/journal.pcbi.1004796
• 发表时间: 2016-03
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Boelen L;O'Neill PK;Quigley KJ;Reynolds CJ;Maillere B;Robinson JH;Lertmemongkolchai G;Altmann DM;Boyton RJ;Asquith B
• 通讯作者: Asquith B

How lymphocytes add up.

淋巴细胞如何累加。

• DOI: 10.1038/ni.3636
• 发表时间: 2016
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Asquith B

Clonality, latency and integration of HTLV-1 in vivo

• DOI: 10.1186/1742-4690-10-s1-o17
• 发表时间: 2013-09-19
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Bangham C;Cook L;Laydon D;Asquith B;Melamed A
• 通讯作者: Melamed A

Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux.

• DOI: 10.1016/j.celrep.2016.11.037
• 发表时间: 2016-12-13
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Ahmed R;Roger L;Costa Del Amo P;Miners KL;Jones RE;Boelen L;Fali T;Elemans M;Zhang Y;Appay V;Baird DM;Asquith B;Price DA;Macallan DC;Ladell K
• 通讯作者: Ladell K

Reconciling Estimates of Cell Proliferation from Stable Isotope Labeling Experiments.

• DOI: 10.1371/journal.pcbi.1004355
• 发表时间: 2015-10
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Ahmed R;Westera L;Drylewicz J;Elemans M;Zhang Y;Kelly E;Reljic R;Tesselaar K;de Boer RJ;Macallan DC;Borghans JA;Asquith B
• 通讯作者: Asquith B