Adaptive immunity against Pneumocystis

针对肺孢子菌的适应性免疫

• 批准号: 8875748
• 负责人: Chad Steele
• 金额: $ 36.2万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875748
• 关键词: Address; Antibody Formation; Attenuated; Automobile Driving; B-Lymphocytes; C57BL/6 Mouse; CCL17 gene; CD19 gene; CD4 Positive T Lymphocytes; Cells; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical; Cyst; Data; Development; Epidemic; Functional disorder; Generations; HIV; Health; Helper-Inducer T-Lymphocyte; Host Defense; IgG1; Immune response; Immunity; Immunosuppression; Inbred BALB C Mice; Individual; Infection; Interferons; Interleukin-10; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Life Cycle Stages; Lung; Macrophage Activation; Mediating; Mediator of activation protein; Mus; Patients; Phenotype; Pilot Projects; Plasma; Play; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii Pneumonia; Population; Predisposing Factor; Production; Proteins; Reporter; Resistance; Role; SCID Mice; STAT4 gene; Serum; Source; Structure of parenchyma of lung; T cell response; TNFSF5 gene; Th2 Cells; Time; Transgenic Mice; adaptive immunity; cytokine; diphtheria toxin receptor; lymph nodes; mRNA Expression; macrophage; novel; pathogen; response; rituximab; tool; transcription factor

DESCRIPTION (provided by applicant): Pneumocystis has risen to the forefront of lethal, opportunistic lung infections as a result of its close association with the HIV epidemic, yet this atypical fungal pathogen is becoming increasingly associated with pharmacologic-driven immunosuppression as well as patients with chronic lung diseases such as COPD. We have recently investigated the role of transcription factor STAT4 in lung immunity to P. murina. We have discovered that Stat4-/- mice on the C57BL/6 background are resistant to P. murina infection while Stat4-/- mice on the BALB/c background are susceptible (Myers et al. submitted, PLoS Pathogens). To our surprise, although having lower Th1 (IFN-y) responses, both BL/6 Stat4-/- and Balb/c Stat4-/- mice unexpectedly demonstrated significantly impaired CD4+ Th2 (IL-4, IL-5 and IL-13) responses in the lung. In spite of this, BL/6 Stat4-/-, but not Balb/c Stat4/-, mice maintained an enhanced M2 macrophage signature (higher Retnla/FIZZ-1 mRNA expression and CCL17/TARC protein levels). In contrast to lung CD4+ T cells, BL/6 Stat4-/- mice demonstrated enhanced CD4+ Th2 responses in the draining lymph nodes and enhanced P. murina-specific IgG1, IgG2b and IgG2c levels in sera, neither of which were observed in BALB/c Stat4-/- mice. Together, these results suggest that protective immunity to P. murina when lung CD4+ T cell responses are impaired involves systemic CD4+ Th2 responses driving optimal B cell responses (Ab production) and a local type 2 response (IL-4/IL-13) in the lungs, which may not be CD4+ T cell in origin, driving M2 macrophage development. This is further supported by new preliminary data showing that compared to non-colonized HIV- infected individuals, Pneumocystis-colonized HIV-infected individuals have significantly lower plasma levels of the Th2 cytokines IL-4, IL-5 and IL-13, but no difference in the levels of IFN-y, IL-17A or IL-10. In preliminary studies, we show that CD4(-)/CD49b(-)/SiglecF(-)/ICOS(+) innate helper type 2 cells were significantly increased in lung tissue of C57BL/6 mice at 2 weeks post-P. murina challenge, suggesting a potential role for this cell population in generating type 2 responses in the lung during P. murina infection. In other studies, employing CD19-DTR mice, which are CD19-Cre mice crossed with Cre-inducible diphtheria toxin receptor (DTR) transgenic mice, we found that CD4+ Th1 and Th2 responses were attenuated in the lymph nodes of mice when B cells were depleted prior to P. murina infection, yet B cell depletion resulted in enhanced CD4+ Th2 and Th17 responses in the lung. Collectively, our data leads us to hypothesize that the generation of type 2 and Th2 responses mediate protective lung immunity against Pneumocystis. To address this hypothesis, we have proposed the following two independent, interrelated Aims: (1) to define the development of local and systemic type 2/Th2 responses during P. murina lung infection and (2) define the role of B cells in the development of local and systemic CD4+ T cell responses during P. murina lung infection.

描述（由申请人提供）：由于肺孢子菌与 HIV 流行密切相关，因此它已成为致命性机会性肺部感染的最前线，但这种非典型真菌病原体与药物驱动的免疫抑制以及慢性肺病（如慢性阻塞性肺病）患者的关系越来越密切。我们最近研究了转录因子 STAT4 在肺鼠疫免疫中的作用。我们发现，C57BL/6 背景的 Stat4-/- 小鼠对 P. murina 感染有抵抗力，而 BALB/c 背景的 Stat4-/- 小鼠则易感（Myers 等人提交，PLoS Pathogens）。令我们惊讶的是，尽管 BL/6 Stat4-/- 和 Balb/c Stat4-/- 小鼠的 Th1 (IFN-y) 反应较低，但其肺部 CD4+ Th2（IL-4、IL-5 和 IL-13）反应却出乎意料地显着受损。尽管如此，BL/6 Stat4-/-（而非 Balb/c Stat4/-）小鼠仍保持增强的 M2 巨噬细胞特征（较高的 Retnla/FIZZ-1 mRNA 表达和 CCL17/TARC 蛋白水平）。与肺 CD4+ T 细胞相比，BL/6 Stat4-/- 小鼠表现出引流淋巴结中 CD4+ Th2 反应增强，血清中 P. murina 特异性 IgG1、IgG2b 和 IgG2c 水平增强，而在 BALB/c Stat4-/- 小鼠中未观察到这两种情况。总之，这些结果表明，当肺 CD4+ T 细胞反应受损时，对鼠鼠的保护性免疫涉及驱动最佳 B 细胞反应（抗体产生）的全身 CD4+ Th2 反应和肺部局部 2 型反应（IL-4/IL-13），这可能不是起源于 CD4+ T 细胞，驱动 M2 巨噬细胞发育。新的初步数据进一步支持了这一点，该数据显示，与非定植的 HIV 感染个体相比，肺孢子虫定植的 HIV 感染个体的 Th2 细胞因子 IL-4、IL-5 和 IL-13 血浆水平显着降低，但 IFN-γ、IL-17A 或 IL-10 水平没有差异。在初步研究中，我们发现在P后2周，C57BL/6小鼠肺组织中CD4(-)/CD49b(-)/SiglecF(-)/ICOS(+)先天辅助2型细胞显着增加。 murina 挑战，表明该细胞群在 P. murina 感染期间在肺部产生 2 型反应中具有潜在作用。在其他研究中，使用 CD19-DTR 小鼠（即 CD19-Cre 小鼠与 Cre 诱导白喉毒素受体 (DTR) 转基因小鼠）杂交，我们发现，当 B 细胞在白喉鼠感染前被耗尽时，小鼠淋巴结中 CD4+ Th1 和 Th2 反应减弱，但 B 细胞耗尽导致 CD4+ Th2 和 Th17 增强 肺部的反应。总的来说，我们的数据使我们推测 2 型和 Th2 反应的产生介导了针对肺孢子虫的保护性肺免疫。为了解决这一假设，我们提出了以下两个独立、相互关联的目标：(1) 定义鼠肺感染期间局部和全身 2 型/Th2 反应的发展；(2) 定义鼠肺感染期间 B 细胞在局部和全身 CD4+ T 细胞反应发展中的作用。