Function of Siglec 5 in T cell activation.

Siglec 5 在 T 细胞激活中的功能。

• 批准号: 10373619
• 负责人: MAKIO IWASHIMA
• 金额: $ 18.45万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-14 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373619
• 关键词: Adult; Antibodies; Antigen Receptors; Antigens; Binding; Binding Proteins; Biological Assay; Birth; Blood; Blood Cells; C-Type Lectins; CD8-Positive T-Lymphocytes; Cell Line; Cell Surface Proteins; Cell Wall; Cell surface; Cells; Cellular Metabolic Process; Child; Complement; Complement Factor H; Complex; Cytoplasmic Tail; Data; Disease; Family; Gene Expression; Goals; Gram-Positive Bacteria; Health; Healthcare; Human; ITIM; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunization; Immunocompetent; Immunoglobulin A; Immunoglobulin Constant Region; Immunoglobulins; Impairment; In Vitro; Infant; Infant Care; Infection; Inflammation; Innate Immune Response; Integral Membrane Protein; Integration Host Factors; Investigation; Lead; Lectin; Life; Measures; Mediating; Memory; Meningitis; Methods; Modification; Mus; Myeloid Cells; Neurologic; Neurons; Neutrophil Activation; Newborn Infant; Perinatal; Premature Infant; Production; Proteins; Recombinants; Reporting; Rest; Role; Savings; Sepsis; Sequence Alignment; Sialic Acids; Signal Transduction; Streptococcal Infections; Streptococcus CAMP protein; Streptococcus Group B; Structure; Survivors; Symptoms; System; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Transcription Factor AP-1; Transcriptional Activation; Tyrosine; Umbilical Cord Blood; Vaccines; Woman; Work; adaptive immune response; base; cell growth; commensal bacteria; complement system; crosslink; cytokine; effector T cell; fetal; granulocyte; humanized mouse; immune checkpoint; improved; in vivo; infant death; knockout gene; macrophage; member; microorganism; monocyte; neonatal infection; neonatal sepsis; neonate; neutrophil; novel therapeutic intervention; nuclear factors of activated T-cells; pathogen; peripheral blood; prevent; programmed cell death protein 1; protein expression; sialic acid binding Ig-like lectin; single-cell RNA sequencing; transcription factor; urogenital tract

Group B Streptococcus (GBS ) is a common commensal bacterium for healthy adults. Approximately 20% of women are infected with GBS in the genitourinary tract without symptoms. However, GBS can cause serious disease in newborn infants. A majority of newborn infants from colonized women get infected with GBS, and about 1% of these infants develop sepsis. Indeed, GBS is a leading cause of invasive infections in infants. GBS infection can be lethal for preterm babies. Moreover, approximately 50% of GBS meningitis survivors suffer lifelong neurological impairment. Thus, it is critically important to understand how GBS colonizes infants and what causes invasive infection by GBS to improve the health care of newborns. Infants have a suppressed immune system which makes them highly vulnerable to infections and limits their immune responses to protective and life-saving vaccines. Both adaptive and innate immune responses in the infant are less effective than those in adult. However, how infant immunity differs from adult immunity in understudies and requires more investigations. GBS has unique capabilities to modulate the human immune system. One such mechanism is the immune inhibition by GBS's cell wall-anchored β–protein. This protein binds to a complement regulatory factor H and the constant region of IgA. Moreover, the GBS β protein binds a C-type Sialic acid-binding immunoglobulin-like lectin 5 (Siglec) 5. Siglec 5 is a cell surface protein expressed by many types of myeloid cells and has a cytoplasmic domain with two immunosuppressive motifs: immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). Siglec 5 was shown to suppress activation of neutrophils and macrophages but was reported previously not expressed by human T cells. Importantly, our sequence alignment analysis showed that the cytoplasmic region of Siglec 5 is closely related to a prototypic immune checkpoint molecule PD-1. To test if GBS modulates perinatal immune responses by β protein-Siglec 5 interactions, we examined the expression of Siglec 5 by cord blood cells in our preliminary study. Unlike previous reports, our data show that a majority of activated cord blood and adult blood T cells express Siglec 5. Siglec 5 expressions in a T cell line inhibited antigen receptor-induced activation of transcription factors. Moreover, recombinant GBS β protein suppressed primary T cell responses, especially Th1 type cytokine productions. Thus, Siglec 5 is a potential immune checkpoint molecule that was not previously recognized. Based on these data, we hypothesize that GBS inhibits activation of perinatal T cells upon infection by β protein-Siglec 5 interactions and reduces adaptive immune responses. In this study, we aim to pursue the following two questions. (1) How does the GBS β protein change T cell activation? (2) Is Siglec 5 required for the T cell suppression by GBS-β protein?

B族链球菌（GBS）是健康成人常见的肠道细菌。大约20%的 妇女在泌尿生殖道感染GBS而没有症状。然而，GBS可导致严重的 新生儿的疾病。大多数来自殖民地妇女的新生儿感染了GBS，并且 这些婴儿中约有1%发展为败血症。事实上，GBS是婴儿侵袭性感染的主要原因。GBS 感染对早产儿是致命的。此外，大约50%的GBS脑膜炎幸存者患有 终身神经损伤因此，了解GBS如何在婴儿中定植是至关重要的， 是什么导致了GBS的侵袭性感染，以改善新生儿的卫生保健。 婴儿的免疫系统受到抑制，这使得他们非常容易受到感染和限制。 他们对保护性和拯救生命的疫苗的免疫反应。获得性和先天性免疫反应， 婴儿的效果不如成人。然而，婴儿免疫力与成人免疫力的不同之处在于， 需要更多的调查。 GBS具有调节人类免疫系统的独特能力。一种这样的机制是 GBS细胞壁锚定β蛋白的免疫抑制作用。这种蛋白质与补体调节因子结合， 因子H和伊加的恒定区。此外，GBS β蛋白结合C-型唾液酸结合蛋白。 免疫球蛋白样凝集素5（Siglec）5. Siglec 5是由许多类型的髓样细胞表达的细胞表面蛋白。 细胞，并具有两个免疫抑制基序的胞质结构域：基于免疫受体酪氨酸的 抑制基序（ITIM）和基于免疫受体酪氨酸转换基序（ITSM）。Siglec 5显示， 抑制嗜中性粒细胞和巨噬细胞活化，但以前报道人T细胞不表达 细胞重要的是，我们的序列比对分析表明Siglec 5的胞质区域与其在细胞内的表达密切相关。 与原型免疫检查点分子PD-1有关。 为了测试GBS是否通过β蛋白-Siglec 5相互作用调节围产期免疫应答，我们检查了 我们对脐血细胞表达Siglec 5进行了初步研究。与之前的报告不同，我们的数据显示， 大多数活化的脐带血和成人血液T细胞表达Siglec 5。T细胞中的Siglec 5表达 线抑制抗原受体诱导的转录因子的激活。此外，重组GBS β 蛋白质抑制初级T细胞应答，尤其是Th 1型细胞因子的产生。因此，Siglec 5是一种 潜在的免疫检查点分子，以前没有认识到。 基于这些数据，我们假设GBS抑制了β-CD感染后围产期T细胞的活化， 蛋白质-Siglec 5相互作用并减少适应性免疫应答。在这项研究中，我们的目标是追求 以下两个问题。(1)GBS β蛋白如何改变T细胞活化？(2)是否需要Siglec 5 GBS-β蛋白对T细胞的抑制作用