SIRPgamma: a novel checkpoint regulator of effector responses from human T-cells

SIRPgamma：人类 T 细胞效应反应的新型检查点调节剂

• 批准号: 10576554
• 负责人: Sushmita Sinha
• 金额: $ 37.88万
• 依托单位: TEXAS WOMAN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-11 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576554
• 关键词: Acceleration; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19 pandemic; Cell physiology; Cell secretion; Cell surface; Cells; Cytomegalovirus; Disease; Environment; Epitopes; Exhibits; Genes; Goals; Human; Immune; Immune response; Immune system; Immunology; In Vitro; Individual; Individual Differences; Infection; Inflammation; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Integration Host Factors; Link; Mediating; Mus; Myelin; Nature; Outcome; Pathogenicity; Phenotype; Play; Process; Proliferating; Proteins; Regulation; Relapsing-Remitting Multiple Sclerosis; Research; Research Project Grants; Rodent; Role; SARS-CoV-2 P.1; SHPS-1 protein; Shapes; Sorting; Surface; T cell response; T-Lymphocyte; Testing; Tetanus Toxoid; Texas; Universities; Vaccination; Variant; Woman; antigen-specific T cells; autoreactive T cell; cytokine; effector T cell; experience; genetic variant; graduate student; immunoregulation; in vivo; insight; inter-individual variation; novel; novel strategies; overexpression; patient oriented research; pharmacologic; response; risk variant; tissue injury; transcription factor; undergraduate student; vaccine response

Abstract A key unresolved question in immunology is: why do some individuals mount a balanced immune response that eliminates infection with no harm to host cells, whereas others have exaggerated immune responses that can cause significant tissue injury and precipitate autoimmunity? This question raises an unprecedented need to better understand the host mechanisms involved in fine-tuning immune responses in humans. T cells play a critical role in shaping a balanced immune response to antigens by directly recognizing molecules expressed on the cell surface and secreting factors that drive or dampen the inflammatory responses. Signal regulatory protein gamma (SIRP) is an immunomodulatory protein that is uniquely expressed on the cell surface of human T cells. Variants in the SIRPG gene have been associated with type 1 diabetes, relapsing remitting multiple sclerosis and maintaining a vaccine response long-term. However, how SIRP mechanistically contributes to inflammation remains unclear because we do not fully understand its function in the immune system. The overall goal of this research is to understand whether inter-individual differences in SIRP expression regulates the effector responses in human T cells. Previously we found that an autoimmunity risk variant in SIRP correlates with reduced expression of SIRP on the T-cells, and that T cells with less SIRP on the cell surface exhibit heightened effector status. This exciting discovery suggest that perturbations in SIRP levels may lead to immune dysregulation during infections and autoimmunity. To test this we will investigate whether intrinsic dysregulation in SIRP expression on naïve T cells accelerates their conversion into terminal effectors, thus driving hyper- proinflammatory responses. These studies will determine if SIRP plays a causative role in determining the magnitude and nature of effector responses from T cells. Given the association of SIRP with multiple autoimmune diseases and vaccine response, understanding the role of SIRP in immune regulation could significantly impact treatment in infection and autoimmunity.

摘要 免疫学中一个关键的未解决的问题是：为什么有些人会产生 平衡的免疫反应，消除感染而不伤害宿主细胞， 而另一些则有过度的免疫反应， 损伤和沉淀性自身免疫？这个问题提出了前所未有的需要， 更好地了解宿主机制参与微调免疫反应， 人类T细胞在形成对抗原的平衡免疫反应中起着关键作用 通过直接识别细胞表面表达的分子并分泌因子 驱动或抑制炎症反应的机制。信号调节蛋白γ (SIRP是一种独特表达于细胞表面的免疫调节蛋白 人类T细胞。SIRPG基因的变异与1型糖尿病相关， 糖尿病、复发缓解型多发性硬化症和维持疫苗反应 长期的然而，SIRP是如何在炎症机制上起作用的， 这是因为我们不完全了解它在免疫系统中的功能。的 这项研究的总体目标是了解是否在个体间的差异， SIRP β表达调节人T细胞中的效应子应答。以前我们 发现SIRP β中的自身免疫风险变体与SIRP β的表达减少相关， SIRP在T细胞上的表达，并且在细胞表面具有较少SIRP表达的T细胞表现出 增强效应器状态。这一令人兴奋的发现表明，SIRP中的扰动 在感染和自身免疫过程中，这些水平可能导致免疫失调。测试 因此，我们将研究SIRP表达的内在失调是否在幼稚T细胞上 细胞加速其转化为终端效应器，从而驱动超 促炎反应这些研究将确定SIRP是否起致病作用， 在决定T细胞效应反应的大小和性质中的作用。给定 SIRP与多种自身免疫性疾病和疫苗应答的关系， 了解SIRP β在免疫调节中的作用可以显著影响 治疗感染和自身免疫。