The canonical (caspase-1) and noncanonical (caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce pyroptosis.Whereas caspase-l processes IL-1β and IL-18 for maturation, no cytokine target has been firmly established for LPS-activated caspase-4/5/11. Here we show that activated human caspase-4, but not mouse caspase-ll, directly and efficiently processes IL-18 in vitro and during bacterial infections, which mainly occurs in epithelial cells. Crystal structure of the caspase-4/pro-IL-18 complex reveals a binary substrate-recognition mechanism, including a unique exosite that binds to a specific structure formed jointly by the propeptide and post-cleavage-site sequences in pro-IL-18. In caspase-ll,a structural deviation around the exosite underlies its inability to target pro-IL-18,which can be restored by rationally designed mutations. The structure of pro-IL-18 features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL-18Ra receptor. Meanwhile,we also find that GSDMD activation by LPS-ligated caspase-4/llspecifically in brain endothelial cells, but not TLR4-induced cytokines, mediates BBB (blood brain barrier) breakdown in response to circulating LPS or during LPS-induced sepsis. Electron microscopy re- cords ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions, and vasculature detachment from basement membrane. Delivery of active GSDMD into brain endothelial cells bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB, which is blocked by a GSDMD-neutralizing nanobody expressed in brain endothelial cells. These findings together shift the paradigm in the understanding of noncanonical-inflam-masome-mediated antibacterial defenses and sepsis.

目前，在T细胞耗竭研究领域，普遍认为肿瘤情形下，肿瘤抗原特异性T细胞分化为具有耗竭性质的耗竭前体细胞及终末耗竭细胞，而不会分化为记忆性T细胞。但随着肿瘤记忆性T细胞的发现，该观点可能需要修正。报告人将就这些关键T细胞亚群的分化关系及其对PD-1免疫治疗的响应进行讨论。

免疫识别是免疫学研究最核心的科学问题。免疫应答和炎症反应起始于免疫细胞通过免疫识别受体对特定抗原或信号的识别和感应，因此免疫识别受体在免疫应答和炎症发生中发挥关键作用。实际上，过去20年当中陆续发现了超过50种固有免疫识别受体，包括Toll样受体、RIG-I样受体、DNA识别受体等，且证明其在病原微生物识别及感染性炎症和疾病发生中发挥关键作用。这些受体的发现极大地促进了我们对于抗感染免疫和感染性疾病发生机制的了解。除病原微生物外，机体在细胞应激、组织损伤、代谢异常、情感应激时产生的一些内源性物质也可激活固有免疫反应并诱发炎症反应。这些内源性物质被称为“危险信号”，其识别或感应受体被成为“危险识别/感应受体”，而其诱发的炎症反应被称为“无菌性炎症”。实际上，无菌性炎症在许多人类重大疾病，比如肿瘤、神经退行性疾病、代谢性疾病、心血管疾病等的发生发展过程中起重要作用，但相对于感染性炎症，其发生机制尚不清楚，也尚缺乏靶向无菌性炎症的有效手段。本报告将介绍实验室在危险感应受体的发现、无菌性炎症的发生及疾病机制研究方面的进展。

免疫受体是免疫细胞感知环境信号并发挥生理功能的基础。其成员主要包括表达在细胞表面的抗原受体、共刺激受体、共抑制受体、FC受体、KIR受体、补体受体、细胞因子受体等家族成员。免疫受体按照其功能，可分为活化型和抑制型两大类，协同调控免疫反应的有效性和精准性。免疫受体功能异常会导致肿瘤、感染、自身免疫病、免疫缺陷等重大疾病。在临床应用上，基于免疫受体的疗法已经成为一线药物。目前全球销售量第一的药物即为PD-1的阻断性抗体。此外，基于工程化免疫受体的CAR-T、TCR-T细胞疗法发展迅速，在国内外已获批多类产品，有望成为新一代的主流药物。本报告将讨论免疫受体中普遍存在的一类信号模体：碱性氨基酸富集序列（Basic residue Rich Sequence,BRS)。BRS一般为10个氨基酸残基左右的短序列，含净电荷大于等于+2。在溶液中体现为固有无序区，而在与膜脂发生静电结合后往往会产生二级结构。BRS可以与各类蛋白质分子和脂质分子形成动态的静电网络，调控免疫受体的磷酸化、寡聚化、泛素化、机械力转导等过程。BRS的致病突变在多种免疫受体中被报道，证明了其功能重要性。目前BRS的信号功能已经被用于CAR分子设计，开发出了新一代的E-CAR技术，在各类肿瘤模型中能够显著地提高疗效并防止复发。E-CAR的临床试验已经开展，初步的数据证明了其安全性和有效性。

Autoimmune diseases are a heterogeneous group of disorder including systemic lupus erythematosus, rheumatoid arthritis and ankylosing spondylitis, affecting l0.1%of the population worldwide. Clinical features of these diseases are systemic organ impairments, vasculitis and destructive arthritis, associated with immune abnormality and autoantibody production. There are unmet needs in early diagnosis and rational treatment, leading to disability, and increased mortality. Recent improvement has been achieved in better understanding of molecular mechanism and development of promising therapies for these diseases. However, specific biomarkers and targeting treatments are expected clinically to improve the prognosis of these autoimmune conditions, especially in long term remission and immune homeostasis. The lecture will focus on the challenges and opportunities in research of these autoimmune diseases.