Innate-adaptive crosstalk in protective and vaccine-induced immunity to TB

结核病保护性免疫和疫苗诱导免疫中的先天适应性串扰

• 批准号: 9412338
• 负责人: Jyothi Rengarajan
• 金额: $ 62.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9412338
• 关键词: Aftercare; Agonist; Animal Model; Antigens; Attenuated; Biological Assay; CD4 Positive T Lymphocytes; Cell Communication; Cells; Data; Disease; Generations; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunotherapy; Impairment; Individual; Infection; Infection Control; Interferon Type II; Interleukin-17; Knowledge; Lead; Ligands; Light; Link; Lung; Memory; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Pathway interactions; Patients; Phenotype; Predisposition; Public Health; Role; Shapes; T cell response; T memory cell; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Tuberculosis; Tuberculosis Vaccines; Vaccination; Vaccine Design; Vaccine Therapy; Vaccines; clinically relevant; comparative efficacy; design; immunogenicity; improved; in vivo; insight; killings; loss of function mutation; mouse model; mutant; mycobacterial; novel; novel vaccines; protective efficacy; response; tuberculosis immunity; tuberculosis treatment; vaccine efficacy; vaccine-induced immunity

ABSTRACT Developing an effective vaccine for tuberculosis (TB) remains challenging because we do not understand how to improve protective immunity to Mycobacterium tuberculosis (Mtb) infection. While CD4 T cells and IFN- g responses are critical for controlling Mtb infection, they are not sufficient for conferring protective immunity. Moreover, Mtb impairs DC functions, leading to antigen-specific CD4 T cells that are ineffective in controlling infection. Therefore we need to design efficacious vaccines that induce additional DC-T cell responses that confer better protection. There is accumulating evidence that IL-17 and Th17 responses are important for protective immunity to TB in mice and humans but the molecular mechanisms for Th17 generation in TB are not well defined. We previously showed that an avirulent hip1 mutant Mtb strain induces earlier and higher IL-17 responses and attenuated disease, suggesting that wild type Mtb restricts optimal Th17 responses in the lung. Here we present novel data that links the CD40-costimulatory capacity of DCs with Th17 generation during Mtb infection. We show that interaction between CD40 and CD40L is critical for generating antigen-specific IL-17 responses to Mtb and that exogenously engaging CD40 on DCs enhances antigen-specific lung Th17 responses. We propose to test the hypothesis that boosting the CD40-CD40L costimulatory pathway and enhancing Th17 responses will improve protection against TB in mice and that these pathways contribute to immune control in human TB. We will undertake 3 distinct yet complementary approaches consisting of mechanistic studies in the mouse model of TB and clinically relevant studies in human cells. Using a mucosal DC vaccination model, we will test whether boosting CD40-CD40L interactions improves protection and define the Mtb-specific T cell memory responses associated with protective immunity (Aim 1). We will use a BCGDhip1 strain, which induces higher CD40 expression and increased Th1 and Th17 responses, to assess its vaccine efficacy compared to BCG (Aim 2). To expand insights from mice to human TB, we will use ex vivo functional assays to determine whether the capacity of DCs to promote IL-17 is greater in individuals who latently control infection compared to those who develop active TB. (Aim 3). Our studies will provide important mechanistic insights into how Mtb modulates DC-T crosstalk in animal models and human cells and open new avenues to target host pathways that can boost protective immunity and improve vaccine efficacy.

摘要 开发有效的结核病疫苗仍然具有挑战性，因为我们不知道如何做到这一点。 以提高对结核分枝杆菌（Mtb）感染的保护性免疫。虽然CD 4 T细胞和IFN-γ 尽管抗结核抗体应答对于控制Mtb感染至关重要，但它们不足以赋予保护性免疫。 此外，Mtb损害DC功能，导致抗原特异性CD 4 T细胞不能有效地控制肿瘤的发生。 感染因此，我们需要设计有效的疫苗，诱导额外的DC-T细胞应答， 提供更好的保护。越来越多的证据表明，IL-17和Th 17应答对于 在小鼠和人类中对结核病的保护性免疫，但结核病中Th 17产生的分子机制不是 定义明确。我们以前发现，无毒hip 1突变Mtb菌株诱导更早和更高的IL-17， 结果表明，野生型Mtb限制了肺中的最佳Th 17应答。 在这里，我们提出了新的数据，联系CD 40共刺激能力的树突状细胞与Th 17产生在结核分枝杆菌。 感染我们发现，CD 40和CD 40 L之间的相互作用是产生抗原特异性IL-17的关键 和外源性接合DC上的CD 40增强抗原特异性肺Th 17 应答我们建议检验增强CD 40-CD 40 L共刺激通路和 增强Th 17应答将改善小鼠对结核病的保护，这些途径有助于 人类结核病免疫控制。我们将采取三种不同但互补的方法，包括 在小鼠TB模型中的机制研究和在人类细胞中的临床相关研究。 使用粘膜DC疫苗接种模型，我们将测试加强CD 40-CD 40 L相互作用是否改善 保护和定义与保护性免疫相关的Mtb特异性T细胞记忆应答（Aim 1）。 我们将使用BCGDhip 1菌株，其诱导更高的CD 40表达和增加的Th 1和Th 17应答， 以评估其与BCG相比的疫苗效力（目标2）。为了将对小鼠的认识扩展到人类结核病，我们将 使用离体功能测定来确定DCs促进IL-17的能力是否在 与那些发展为活动性结核病的人相比，潜伏控制感染的人。(Aim 3）。我们的研究将 为Mtb如何调节动物模型和人类中的DC-T串扰提供了重要的机制见解 细胞和开辟新的途径，靶向宿主途径，可以提高保护性免疫力和改善疫苗 功效