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 细胞负责检测传染源，无论是细菌、病毒还是寄生虫；它们负责评估这些传染原可能造成的潜在损害，并发起适当的和选择性的免疫反应，以消除传染原，同时对宿主造成最小的损害。 T 细胞在与抗原呈递细胞（专门吞噬外来颗粒、将其消化成更小的碎片并将这些碎片呈递给 T 细胞）形成结合物时做出这一决定。 T 细胞通过刺激其他免疫反应细胞分泌抗体来消除病原体。细胞毒性 T 细胞通过杀死受感染的宿主细胞发挥作用，从而使内部的病原体丧失能力。作为该提案的一部分，这两种细胞类型都将受到研究。 T 辅助细胞在几个小时内做出决定，在此期间，T 细胞通过称为免疫突触的结构与抗原呈递细胞相对应。突触是免疫学家从神经生物学领域偷来的一个术语。神经元通过突触将信号从一根神经传递到另一根神经，这实际上也是免疫细胞的作用。然而，也存在重要的差异。免疫细胞活动性很强，可以穿过淋巴结和不同的组织，例如可能发现感染因子的皮肤和肠道。这种持续的运动对 T 细胞形成稳定突触施加了额外的限制 - 有点像跳伞员在自由落体时试图抓住彼此的手。 p110delta 属于磷酸肌醇 3-激酶（简称 PI3K）的酶家族。我们对小鼠进行了基因改造，其中 p110delta 的基因被修改，使得该酶不再发挥作用。来自此类小鼠的 T 细胞很难与抗原呈递细胞形成缀合物。此外，我们有证据表明，p110delta 缺陷的 T 细胞无法将自身组织成正确的构象，从而无法最大限度地提高其读取和解释抗原呈递细胞提供的信号的能力。这项资助的第一个目的是在分子水平上更全面地表征这些缺陷，因为目前尚不清楚为什么 p110delta 对这些功能如此重要。接下来，我们将确定这对于 T 细胞响应感染因子的能力实际上有多重要。我们还将监测 T 细胞在感染单核细胞增生李斯特氏菌后的反应。这种细菌有时存在于未经高温消毒的奶制品中，例如奶酪，可能导致人类疾病。我们将在取自受感染小鼠的 T 细胞中观察它们是否与 APC 产生功能性缀合物以及它们是否能够做出适当的反应。此外，我们将测试 p110delta 缺陷的 T 细胞是否能够以这样的方式分裂，即一个细胞成为效应细胞（注定寿命短暂，致力于立即消除感染因子），而另一个细胞则成为记忆细胞，在后台等待，并准备在再次遇到特定传染源时提出更立即和有效的应对措施。这个过程是疫苗发挥作用的基础。这些实验将共同研究 p110delta（制药行业正在开发的药物的靶标）如何影响防止反复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