Dissecting the functional impact of natural killer cell receptor variation in cattle.

剖析牛自然杀伤细胞受体变异的功能影响。

基本信息

批准号：
BB/J006211/1
负责人：
John Hammond
金额：
$ 75.98万
依托单位：
The Pirbright Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FJ006211%2F1
关键词：
Dissecting functional impact natural killer

项目摘要

Challenges to the health of an organism are met by the immune system. These challenges can arise from external sources, such as bacteria, viruses, or allergens as well as internal sources such as tumours. Meeting all these challenges is a difficult task and has resulted in a highly complex immune system. Pathogenic invaders are constantly changing in an attempt to avoid immune detection. This in turn drives the immune system, fostering a repetitive cycle of change and adaptation for both the host and pathogen. Diverse receptors expressed on a variety of immune cells are an essential part of this host adaptation. A significant proportion (~5 %) of mammalian genomes is dedicated to the immune system, particularly those immune receptors which form gene clusters and families. Within these families mutation and germ-line recombination creates a source for new genes and new variants of old genes. In fact, immune related genes have diversified more than any other type in mammalian genomes. A distinct set of variable and diverse receptors are expressed on natural killer (NK) cells. NK cells are one of the first responders to pathogens. The magnitude of the NK response subsequently directs how the rest of the immune system responds. NK cells are controlled by some of the most diverse immune receptors identified and are especially important in antiviral immunity. Amongst mammals, cattle have the most diverse NK cell receptor system so far identified. As this system evolved to combat infection, it is essential to examine this system in cattle to understand how these economically crucial animals fight infection. This knowledge will enable applied studies to improve vaccines and breed for disease resistance. This proposal will use information from the cattle genome and high-throughput DNA sequencing technology to completely characterise the NK cell receptor gene families in six Holstein-Friesian dairy cattle. This is an economically important breed in the UK and worldwide. By comparing several animals within this breed we can determine the extent of NK cell receptor diversity. Using knowledge of these receptors, we will determine the molecules that they interact with on infected cells to control NK cell function. This will determine if animals that have dissimilar NK cell receptors are likely to respond differently to infection. Finally, we will infect particular cattle cells that are known to activate NK cells and in turn become activated by NK cells. These will be infected with a known economically important cattle pathogen, bovine herpes virus-1. We will then incubate these infected cells with NK cells that express different NK cell receptor genes. By measuring how these NK cells function and how the infected cells respond, it will be possible to determine if NK cell variation causes different immune responses.Knowledge of how NK cells respond to virus infection depending on their receptors is essential. This fundamental research will allow future examination of how individual animals vary in their response to individual pathogens and vaccination. This will create opportunities to increase the frequency of beneficial genes through genomic selection breeding strategies and more accurately measure how effective vaccines protect animals from pathogen challenge.

免疫系统应对生物体健康的挑战。这些挑战可能来自外部来源，例如细菌，病毒或过敏原以及内部来源，例如肿瘤。应对所有这些挑战是一项艰巨的任务，并导致了高度复杂的免疫系统。病原入侵者正在不断变化，以避免免疫检测。反过来，这驱动了免疫系统，促进了宿主和病原体的变化和适应性的重复循环。在各种免疫细胞上表达的不同受体是该宿主适应的重要组成部分。哺乳动物基因组的显着比例（约5％）专门用于免疫系统，尤其是那些形成基因簇和家族的免疫受体。在这些家庭中，突变和种系重组为新基因和旧基因的新变体创造了来源。实际上，与哺乳动物基因组中的任何其他类型相比，免疫相关的基因多样性多。自然杀手（NK）细胞表达了一组不同的可变和多样化受体。 NK细胞是对病原体的首批反应者之一。 NK响应的大小随后指导其余免疫系统的反应。 NK细胞受到一些鉴定出的最多样化的免疫受体的控制，并且在抗病毒免疫中尤为重要。在哺乳动物中，牛的NK细胞受体系统迄今已确定最多样化。随着该系统的发展为对抗感染，必须检查牛的该系统，以了解这些经济上至关重要的动物如何与感染作斗争。这些知识将使应用研究能够改善疫苗并以疾病抗性繁殖。该建议将使用来自牛基因组和高通量DNA测序技术的信息，以完全表征六个荷斯坦 - 弗里斯奶牛牛中NK细胞受体基因家族。这在英国和全球都是经济上重要的品种。通过比较该品种中的几只动物，我们可以确定NK细胞受体多样性的程度。使用这些受体的知识，我们将确定它们与受感染细胞相互作用以控制NK细胞功能的分子。这将确定具有不同NK细胞受体的动物是否可能对感染有所不同。最后，我们将感染已知会激活NK细胞并被NK细胞激活的特定牛细胞。这些将被已知的经济重要的牛病原体，牛疱疹病毒1感染。然后，我们将与表达不同NK细胞受体基因的NK细胞一起孵育这些感染细胞。通过测量这些NK细胞的功能以及感染细胞的反应方式，可以确定NK细胞变异是否引起不同的免疫反应。了解NK细胞如何根据受体对病毒感染的反应反应。这项基本研究将允许将来检查单个动物对单个病原体和疫苗接种的反应如何变化。这将创造机会通过基因组选择育种策略来增加有益基因的频率，并更准确地衡量有效疫苗如何保护动物免受病原体挑战的影响。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nomenclature for the KIR of non-human species.

DOI：
10.1007/s00251-018-1064-4
发表时间：
2018-09
期刊：
Immunogenetics
影响因子：
3.2
作者：
Robinson J;Guethlein LA;Maccari G;Blokhuis J;Bimber BN;de Groot NG;Sanderson ND;Abi-Rached L;Walter L;Bontrop RE;Hammond JA;Marsh SGE;Parham P
通讯作者：
Parham P

Definition of the cattle killer cell Ig-like receptor gene family: comparison with aurochs and human counterparts.

DOI：
10.4049/jimmunol.1401980
发表时间：
2014-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Sanderson ND;Norman PJ;Guethlein LA;Ellis SA;Williams C;Breen M;Park SD;Magee DA;Babrzadeh F;Warry A;Watson M;Bradley DG;MacHugh DE;Parham P;Hammond JA
通讯作者：
Hammond JA

The evolution of the natural killer complex; a comparison between mammals using new high-quality genome assemblies and targeted annotation

自然杀手复合体的演变；

DOI：
10.1101/069922
发表时间：
2016
期刊：
影响因子：
0
作者：
Schwartz J
通讯作者：
Schwartz J

The evolution of the natural killer complex; a comparison between mammals using new high-quality genome assemblies and targeted annotation.

DOI：
10.1007/s00251-017-0973-y
发表时间：
2017-04
期刊：
Immunogenetics
影响因子：
3.2
作者：
Schwartz JC;Gibson MS;Heimeier D;Koren S;Phillippy AM;Bickhart DM;Smith TP;Medrano JF;Hammond JA
通讯作者：
Hammond JA

Two Lineages of KLRA with Contrasting Transcription Patterns Have Been Conserved at a Single Locus during Ruminant Speciation

反刍动物物种形成过程中，具有对比转录模式的 KLRA 两个谱系在单个基因座上得到了保守