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

由于缺乏有效的疫苗以及耐药和耐多药菌株的增加，导致结核病的结核分枝杆菌（Mtb）感染仍然是全世界死亡的主要原因之一。由于CD1c抗原呈递系统的非多态性特性能够介导对脂质抗原（如富含脂质的结核细胞壁）的反应，同时考虑到与结核病免疫反应相关的高水平免疫异质性，CD1c限制性T细胞成为未来结核病疫苗令人兴奋的潜在靶点。人们认为它们可能在宿主对TB的免疫应答中发挥作用，然而，考虑到很大一部分cd1限制性T细胞是自身反应性的，它们是保护性的还是致病性的尚不清楚。培养cd1c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“CD1c免疫在宿主对结核病的反应中具有保护作用”的假设，我开发了一种生成纯CD1c限制性T细胞系的方法，然后通过将T细胞系与结核分枝杆菌感染的CD1c+靶细胞共培养进行了功能研究。迄今为止收集的数据表明，CD1c限制性T细胞在结核分枝杆菌感染时变得更加活跃，并且具有杀死CD1c+靶标的能力。先前的研究表明，结核分枝杆菌感染导致1组CD1表达下调。这导致人们认为，结核分枝杆菌这样做可能是为了破坏1组cd1介导的免疫反应，使其能够在宿主免疫细胞内存活。为了回答“Mtb感染可以影响抗原提呈细胞CD1表达”的假设，我在适合功能研究的感染多重性（multiplicity of infection， MOI）下用Mtb感染抗原提呈细胞，并测量了1组CD1表达。与未感染的抗原提呈细胞相比，所有1组CD1分子的表达均降低。最近在实验室中使用CD1c-endo四聚体和单细胞TCR测序独立地产生了来自不同供体的多个Vgamma9Vdelta2 TCR，这些TCR被认为是cd1限制性的，令人惊讶的是，因为CD1c不是已知的配体。我也开始了初步的调查，以回答“CD1c是Vgamma9Vdelta2 T细胞的配体”的假设。

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".