Function of Siglec 5 in T cell activation.

Siglec 5 在 T 细胞激活中的功能。

基本信息

批准号：
10665549
负责人：
MAKIO IWASHIMA
金额：
$ 22.3万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-14 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665549
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 Cytoplasm 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 Immunoreceptor Tyrosine-Based Motif Impairment In Vitro Infant Infant Care Infection Inflammation Innate Immune Response Integral Membrane Protein Integration Host Factors Investigation Lectin Life Macrophage Measures Mediating Memory Meningitis Methods Modification Mus Myeloid Cells Neonatal meningitis Neurologic Neurons Neutrophil Activation Newborn Infant Perinatal Premature Infant Production Proteins Recombinants Reporting Rest Role Sepsis Sequence Alignment Sialic Acids Signal Transduction Streptococcal Infections 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 Umbilical Cord Blood Vaccines Woman Work adaptive immune response cell growth commensal bacteria complement system crosslink cytokine effector T cell fetal granulocyte humanized mouse immune checkpoint improved in vivo infant death knockout gene 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 prototype sialic acid binding Ig-like lectin single-cell RNA sequencing transcription factor urogenital tract

项目摘要

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) 是大约 20% 的健康成年人的常见共生细菌。女性在泌尿生殖道感染 GBS 时不会出现任何症状，但 GBS 会导致严重的后果。大多数来自殖民地妇女的新生儿感染 GBS，并且事实上，这些婴儿中约 1% 会患上败血症，GBS 是婴儿侵袭性感染的主要原因。此外，大约 50% 的 GBS 脑膜炎幸存者患有感染。因此，了解 GBS 如何在婴儿和婴儿中定殖是至关重要的。是什么导致 GBS 侵袭性感染，以改善新生儿的医疗保健。婴儿的免疫系统受到抑制，这使得他们极易受到感染并受到限制他们对保护性和挽救生命的疫苗的免疫反应，包括适应性免疫反应和先天性免疫反应。婴儿的免疫力不如成人。但是，婴儿的免疫力与成人的免疫力有何不同。尚待研究并需要更多研究。 GBS 具有调节人体免疫系统的独特能力。 GBS 细胞壁锚定 β 蛋白的免疫抑制作用，该蛋白与补体调节蛋白结合。 H 因子和 IgA 恒定区此外，GBS β 蛋白结合 C 型唾液酸结合。免疫球蛋白样凝集素 5 (Siglec) 5。Siglec 5 是多种骨髓细胞表达的细胞表面蛋白细胞，并具有带有两个免疫抑制基序的细胞质结构域：基于酪氨酸的免疫受体抑制基序 (ITIM) 和基于免疫受体酪氨酸的开关基序 (ITSM) 被证明可以发挥作用。抑制中性粒细胞和巨噬细胞的激活，但之前有报道称人类 T 细胞不表达重要的是，我们的序列比对分析表明 Siglec 5 的细胞质区域紧密相连。与原型免疫检查点分子 PD-1 相关。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反应，我们检查了我们的数据显示，与之前的报告不同，我们的初步研究中脐带血细胞表达 Siglec 5。大多数活化的脐带血和成人血 T 细胞表达 Siglec 5。T 细胞中的 Siglec 5 表达此外，重组 GBS β 线抑制抗原受体诱导的转录因子激活。 Siglec 5 蛋白抑制原代 T 细胞反应，特别是 Th1 型细胞因子的产生。以前未被识别的潜在免疫检查点分子。基于这些数据，我们发现 GBS 抑制 β 感染后围产期 T 细胞的激活蛋白质-Siglec 5 相互作用并减少适应性免疫反应在这项研究中，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？ GBS-β蛋白抑制T细胞？