Investigating the functional role of CD1 expression and defining protective and pathogenic CD1c-immunity in tuberculosis.

研究 CD1 表达的功能作用并定义结核病中的保护性和致病性 CD1c 免疫。

• 批准号: 2449855
• 金额: --
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2449855
• 关键词: Investigating; functional; role; CD1; expression

Due to the lack of an effective vaccine and the rise of drug resistant and multidrug resistant strains, Mycobacterium tuberculosis (Mtb) infection, which causes Tuberculosis (TB), remains one of the leading causes of death worldwide. CD1c-restricted T cells make for exciting potential targets for future TB vaccines due to the ability of the non-polymorphic nature of the CD1c antigen presenting system to mediate responses to lipid antigens, such as those of lipid-rich Mtb cell wall, whilst accounting for the high levels of immune heterogeneity associated with immune response in TB. It is believed that they may play a role in in the host immune response to TB, however, considering a large proportion of CD1crestricted T cells are autoreactive, it is not known if they are protective or pathogenic. Making their study challenging, culturing CD1c-restricted T cells is difficult. To answer the hypothesis "CD1cimmunity is protective during the host response to TB", I have developed a methodology of generating pure CD1c-restricted T cell lines and have then conducted functional studies by co-culturing T cell lines with Mtb infected CD1c+ target cells. Data collected thus far shows that CD1c-restricted T cells become significantly more activated with Mtb infection and have the ability to kill CD1c+ targets. Previous studies have shown that Mtb infection results in a down regulation of group 1 CD1 expression. This has led to suggestions that Mtb may do so in order to subvert group 1 CD1-mediated immune responses enabling it to survive within host immune cells. To answer the hypothesis "Mtb infection can influence the CD1 expression of antigen presenting cells", I infected antigen presenting cells with Mtb at a multiplicity of infection (MOI) suitable for functional studies and measured group 1 CD1 expression. Compared to uninfected antigen presenting cells, expression of all group 1 CD1 molecules was reduced. Recent work in the lab using CD1c-endo tetramers and single cell TCR sequencing has independently generated multiple Vgamma9Vdelta2 TCRs derived from different donors which are believed to be CD1crestricted, surprising, as CD1c is not a known ligand. I have also begun preliminary investigations to answer the hypothesis "CD1c is a ligand for Vgamma9Vdelta2 T cells".

由于缺乏有效的疫苗以及耐药和多药耐药菌株的增加，导致结核病（TB）的结核分枝杆菌（Mtb）感染仍然是全世界死亡的主要原因之一。由于CD 1c抗原呈递系统的非多态性性质能够介导对脂质抗原（例如富含脂质的Mtb细胞壁的那些）的应答，同时解释与TB中的免疫应答相关的高水平免疫异质性，因此CD 1c限制性T细胞成为未来TB疫苗的令人兴奋的潜在靶点。据信它们可能在宿主对TB的免疫应答中起作用，然而，考虑到大部分CD 1限制性T细胞是自身反应性的，尚不清楚它们是保护性的还是致病性的。培养CD 1c限制性T细胞是困难的，这使得他们的研究具有挑战性。为了回答“CD 1c免疫在宿主对TB的应答期间是保护性的”这一假设，我开发了一种产生纯CD 1c限制性T细胞系的方法，然后通过将T细胞系与Mtb感染的CD 1c+靶细胞共培养来进行功能研究。迄今为止收集的数据显示，CD 1c限制性T细胞在Mtb感染时变得更加活化，并且具有杀死CD 1c+靶点的能力。先前的研究表明，结核分枝杆菌感染导致第1组CD 1表达下调。这导致Mtb可能这样做是为了破坏第1组CD 1介导的免疫应答，使其能够在宿主免疫细胞内存活。为了回答“Mtb感染可以影响抗原呈递细胞的CD 1表达”的假设，我以适合于功能研究的感染复数（MOI）用Mtb感染抗原呈递细胞并测量组1 CD 1表达。与未感染的抗原呈递细胞相比，所有第1组CD 1分子的表达均降低。最近在实验室中使用CD 1c-内四聚体和单细胞TCR测序的工作已经独立地产生了来自不同供体的多个V γ 9 V δ 2 TCR，这些TCR被认为是CD 1c限制的，这是令人惊讶的，因为CD 1c不是已知的配体。我也已经开始初步研究，以回答“CD 1c是V γ 9 V δ 2 T细胞的配体”的假设。