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

摘要 免疫学中一个关键的悬而未决的问题是：为什么有些人会登上 平衡的免疫反应在不损害宿主细胞的情况下消除感染， 而另一些则具有夸大的免疫反应，这可能会导致显著的组织 损伤并引发自身免疫？这个问题提出了前所未有的需要 更好地了解微调免疫反应所涉及的宿主机制 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和分泌因子 驱动或抑制炎症反应的物质。信号调节蛋白-γ (Sirp)是一种在细胞表面唯一表达的免疫调节蛋白 人类T细胞。SIRPG基因的变异与1型有关 糖尿病、复发缓解多发性硬化症和维持疫苗反应 长期的。然而，sirp如何机械地促进炎症仍然存在。 不清楚是因为我们还不完全了解它在免疫系统中的功能。这个 这项研究的总体目标是了解个体之间的差异是否 Sirp表达调控人T细胞的效应反应。以前我们 发现Sirp中的一种自身免疫风险变异体与表达减少有关 T细胞表面Sirp较少，T细胞表面Sirp较少 增强效应器状态。这一令人兴奋的发现表明，Sirp中的微扰 水平可能会导致感染和自身免疫过程中的免疫失调。为了测试 我们将调查在幼稚T细胞上Sirp表达的内在失调 细胞加速转化为终端效应器，从而推动超 促炎反应。这些研究将确定Sirp是否在 在确定T细胞效应反应的大小和性质方面的作用。vt.给出 Sirp与多种自身免疫性疾病和疫苗应答的关系 了解Sirp在免疫调节中的作用可能会显著影响 感染和自身免疫方面的治疗。

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.