PI3K signalling at the immune synapse asymmetric division and immunological memory.

免疫突触不对称分裂和免疫记忆的 PI3K 信号传导。

• 批准号: BB/F015461/1
• 负责人: Klaus Okkenhaug
• 金额: $ 97.59万
• 依托单位: Babraham Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF015461%2F1
• 关键词: PI3K; signalling; immune; synapse; asymmetric

T helper cells are master cells of the immune response. T cells are responsible for detecting infectious agents, be they bacteria, viruses or parasites; they are responsible for assessing the potential damage these infectious agents can cause, and to mount proportional and selective immune response to get rid of the infectious agent while causing minimal damage to the host. The T cells make this decision as they form conjugate with antigen presenting cells - that is cells that are specialised in devouring foreign particles, digesting them in to smaller fragments, and presenting these fragments to T cells. T cells respond by stimulating other cells of the immune response to secrete antibodies that eliminate the pathogen. Cytotoxic T cells act by killing infected host cells, thus incapacitating the pathogen inside. Both these cell types will be investigated as part of this proposal. T helper cell makes their decisions over several hours during which the T cell corresponds with an antigen presenting cell though a structure called the immune synapse. The synapse is a term immunologists have stolen from the field of neurobiology. Neurons transmit signals from one nerve to another through synapses, which in fact is what immune cells do as well. However, there are important differences. Immune cells are highly motile and travel through the lymph nodes and through different tissues, such as the skin and gut where infections agents may be found. This constant movement places additional constraints on T cells to form stable synapses - a bit like parachutists trying to grab each others hands while in freefall. p110delta belongs to a family of enzymes called phosphoinositide 3-kinases (PI3Ks for short). We have engineered mice in which the gene for p110delta is modified such that the enzyme is no longer functional. T cells from such mice are poor at forming conjugates with antigen presenting cells. Moreover, we have evidence that p110delta-deficient T cells fail to organise themselves in the right conformation to maximise their ability to read and interpret the signals provided by the antigen presenting cells. The first purpose of this grant is to more fully characterise these defects at the molecular level as it is at present not obvious why p110delta should be important for these functions. Next, we will determine how important this actually is for the ability of T cells to respond to infectious agents. We will also monitor how T cells respond after infection with a bacterium called Listeria monocytogenes. This bacterium is sometimes found in unpasteurised milk products, such as cheese, and can cause disease in humans. We will observe in T cells taken from infected mice whether they make functional conjugates with APCs and if they are capable of responding appropriately. In addition, we will test if p110delta-deficient T cells can divide in such a way that one cell becomes an effector cell (destined for a short life dedicated to immediate elimination of the infectious agent), whereas the other cell becomes a memory cell that waits in the background and is prepared to raise an even more immediate and effective response should the particular infectious agent be encountered again. This process is the basis for how vaccines work. Together, these experiments will examine how p110delta, a target for drugs being developed by the pharmaceutical industry, affects fundamental immune responses that protect from recurrent infections.

T辅助细胞是免疫反应的主细胞。 T细胞负责检测传染剂，无论是细菌，病毒还是寄生虫。他们负责评估这些传染性药物可能造成的潜在损害，并安装成比例和选择性的免疫反应，以消除感染剂，同时对宿主造成最小的损害。 T细胞在与抗原呈递细胞形成共轭时做出了这一决定，即专门用于吞噬异物颗粒的细胞，将其消化成较小的片段，并将这些片段呈现给T细胞。 T细胞通过刺激对消除病原体的分泌抗体的免疫反应的其他细胞的反应。细胞毒性T细胞通过杀死受感染的宿主细胞起作用，从而使病原体内部无能为力。这两种细胞类型都将作为该提案的一部分进行研究。 T辅助细胞在几个小时内做出决策，在此过程中，T细胞通过称为免疫突触的结构对应于抗原呈现细胞。突触是一名术语免疫学家从神经生物学领域偷来的。神经元通过突触将信号从一个神经传递到另一个神经，实际上是免疫细胞所做的。但是，存在重要的差异。免疫细胞是高度运动的，并穿过淋巴结和不同的组织，例如可以发现感染剂的皮肤和肠道。这种不断的运动在T细胞上放置了其他约束，以形成稳定的突触 - 有点像试图在自由落体时抓住彼此的跳伞者。 p110delta属于一种称为磷酸肌醇3-激酶（简称PI3K）的酶家族。我们已经设计了p110delta的基因，以使酶不再具有功能。在与抗原呈递细胞形成结合物时，来自此类小鼠的T细胞很差。此外，我们有证据表明，p110delta缺陷型T细胞无法以正确的构型组织自己，以最大程度地提高其阅读和解释抗原呈递细胞提供的信号的能力。该赠款的第一个目的是更充分地在分子水平上表征这些缺陷，因为目前尚不明显为什么P110delta对于这些功能应该很重要。接下来，我们将确定这对T细胞对感染剂的反应能力的实际重要性。我们还将监测T细胞在感染单核细胞增生李斯特菌的细菌后如何反应。该细菌有时在未经随意的牛奶产品（例如奶酪）中发现，并可能引起人类疾病。我们将在从受感染的小鼠中获取的T细胞中观察到它们是否与APC产生功能性共轭以及它们是否能够适当响应。此外，我们将测试P110DELTA缺陷型T细胞是否可以分裂，使一个细胞成为效应细胞（注定要短暂生命，致力于立即消除传染性剂），而另一个细胞会成为后台等待的记忆细胞，并准备好即时有效的响应，以便更有效地响应，应再次征收特定的感染剂。此过程是疫苗工作方式的基础。这些实验将共同研究制药行业开发的药物的P110DELTA如何影响防止复发感染的基本免疫反应。

项目成果

Signaling by the phosphoinositide 3-kinase family in immune cells.

• DOI: 10.1146/annurev-immunol-032712-095946
• 发表时间: 2013
• 期刊: Annual review of immunology
• 影响因子: 29.7
• 作者: Okkenhaug K

Non-Invasive Multiphoton Imaging of Islets Transplanted Into the Pinna of the NOD Mouse Ear Reveals the Immediate Effect of Anti-CD3 Treatment in Autoimmune Diabetes.

• DOI: 10.3389/fimmu.2018.01006
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Benson RA;Garcon F;Recino A;Ferdinand JR;Clatworthy MR;Waldmann H;Brewer JM;Okkenhaug K;Cooke A;Garside P;Wållberg M
• 通讯作者: Wållberg M

Pten loss in CD4 T cells enhances their helper function but does not lead to autoimmunity or lymphoma.

• DOI: 10.4049/jimmunol.1102116
• 发表时间: 2012-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Soond DR;Garçon F;Patton DT;Rolf J;Turner M;Scudamore C;Garden OA;Okkenhaug K
• 通讯作者: Okkenhaug K

PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.

• DOI: 10.1182/blood-2009-07-232330
• 发表时间: 2010-03-18
• 期刊: Blood
• 影响因子: 20.3
• 作者: Soond DR;Bjørgo E;Moltu K;Dale VQ;Patton DT;Torgersen KM;Galleway F;Twomey B;Clark J;Gaston JS;Taskén K;Bunyard P;Okkenhaug K
• 通讯作者: Okkenhaug K

The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development.

• DOI: 10.1126/scisignal.2001104
• 发表时间: 2010-08-10
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Ramadani F;Bolland DJ;Garcon F;Emery JL;Vanhaesebroeck B;Corcoran AE;Okkenhaug K
• 通讯作者: Okkenhaug K