S1PR2

编辑丨王多鱼 排版丨水成文 机体被同一病原微生物再次感染时，免疫系统能够通过比第一次应答更快、更强的免疫反应来控制感染、减轻或阻止疾病发展。这种免疫记忆力，主要依靠能识别该病原的淋巴细胞承载。理解免疫记忆如何产生，对于开发抗感染疫苗和治疗自身免疫性疾病都具有重要的理论和实践指导意义。 记忆 B 淋巴细胞（Memory B cell，MBC）是抗体免疫记忆的承载者之一，往往需要经历被称为“生发中心”的反应才真正能够发挥记忆功能。在“生发中心”里，高度集聚的 B 细胞高速增殖并反复经历基于亲和力的相互竞争和筛选。在竞争中胜出的细胞会被不断输出成为记忆 B 细胞和浆细胞，但这个过程背后的细胞发育和命运决定机制还很不清楚。  2025 年 3 月 18 日，清华大学医学院祁海教授团队（罗晓翠和侯小筱为论文共同第一作者）在 Immunity 期刊发表了题为：An interleukin-9-ZBTB18 axis promotes germinal center development of memory B cells 的研究论文。 该研究首次报道了 T 细胞分泌的白细胞介素-9（IL-9）通过诱导转录因子 ZBTB18 表达，促进生发中心（GC）B 细胞向记忆 B 细胞的定向分化与功能成熟。 记忆 B 淋巴细胞（Memory B cell，MBC）从生发中心（germinal center，GC）发育的过程，涉及细胞周期、定位和存活方面的深刻变化。 在这项最新研究中，鉴于白细胞介素-9（IL-9）对于正常的抗体二次应答的重要性，研究团队重点关注了 IL-9 诱导记忆程序的机制。 通过过继移植和辐射嵌合体模型，研究团队发现， T 细胞来源的 IL-9 对记忆 B 淋巴细胞的发育和功能是必需的。相比之下，缺乏 IL-9 的 B 细胞生成的功能正常的记忆 B 淋巴细胞能够正常支持抗体的二次应答。 IL-9 诱导生发中心记忆前体细胞和记忆 B 淋巴细胞中转录抑制因子 ZBTB18 的表达。ZBTB18 对初始 B 细胞的活化和生发中心的形成并非必需，但其对于生发中心来源的记忆 B 淋巴细胞的发育是必需的。ZBTB18 直接抑制了一组编码细胞周期蛋白和细胞周期蛋白依赖性激酶、促凋亡基因 Bid 和 Casp3 以及生发中心滞留因子 S1pr2 基因的表达。缺乏由 ZBTB18 介导的 IL-9 指导或内在编程会损害生发中心来源的记忆 B 淋巴细胞发育和抗体二次应答。 该研究的核心发现： T 细胞来源的 IL-9 指导初次应答中生发中心的记忆 B 淋巴细胞（MBC）发育； IL-9 诱导 MBC 前体细胞中 ZBTB18 的表达； ZBTB18 促进 MBC 前体细胞的细胞周期退出、细胞存活以及从生发中心的离开； ZBTB18 介导 IL-9 对 MBC 发育的诱导作用。 因此，IL-9-ZBTB18 信号轴指导了生发中心中功能性 B 细胞记忆的形成。这些发现破解了 B 细胞免疫记忆形成的关键分子机制，为通过操控免疫记忆而强化疫苗、创新免疫治疗提供了新靶点。 论文链接： https://www.cell.com/immunity/fulltext/S1074-7613(25)00088-3 设置星标，不错过精彩推文 开放转载 欢迎转发到朋友圈和微信群  微信加群  为促进前沿研究的传播和交流，我们组建了多个专业交流群，长按下方二维码，即可添加小编微信进群，由于申请人数较多，添加微信时请备注：学校/专业/姓名，如果是PI/教授，还请注明。 点在看，传递你的品味

引言 组织驻留性免疫细胞对维持机体稳态和对抗感染具有重要意义。然而，我们对于组织驻留免疫细胞的构成和特性仍缺乏足够的理解。关于组织驻留免疫细胞的认识大多来自巨噬细胞的研究，在胚胎发育早期，造血祖细胞种植在各种组织并特化发育为独特的巨噬细胞【1】。组织驻留性记忆细胞（tissue-resident memory，Trm）的发现打破了αβT细胞的循环迁移模型【2】。抗原经历的记忆T细胞会长期甚至无限期停留在抗原暴露组织，一旦抗原再次出现迅速做出应答反应。近几年，多篇文献报道组织驻留Treg的重要作用【3】，例如脂肪Treg的维持机体代谢稳态作用【4,5】、肌肉Treg参与肌肉修复【6】、脑Treg驱动少突胶质细胞分化、皮肤Treg抑制纤维化【7,8】和子宫Treg促进胎儿生长【9】等。在表型上类似于Trm，组织Treg同样表达CD69、CD103、CD11a和PD-1。虽然这种相似性支持组织Treg的定植特化模型，但尚缺乏直接的数据。 近日，英国剑桥大学病理学系Adrian Liston研究团队在Immunity杂志在线发表题为The tissue-resident regulatory T cell pool is shaped by transient multi-tissue migration and a conserved residency program的研究文章。该研究通过高维流式细胞术、TCR-seq、RNA-seq和parabiosis分析，向传统定植特化的长期驻留模型发起挑战，提出组织驻留Treg的泛组织迁移模型，为组织Treg提供另一种理解。 团队首先在小鼠的48个组织中分析Treg的浸润和表型，包括淋巴、非淋巴和肠相关组织。结果发现Treg在各组织占CD4+T细胞的10-20%，在骨髓、皮肤和舌头占比上升到50%。在绝对数量上，淋巴组织Treg为104-107，肠相关组织为103-105，非淋巴组织为10-104。整体上看，淋巴组织Treg占机体Treg的98%，肠相关组织为0.8%，非淋巴组织为0.3%。流式降维分析将Treg分为5群，包括血液、淋巴、骨髓、组织和肠相关Treg，这种分群大致反应解剖位置，但也存在例外如胃Treg聚类到组织Treg。进一步分析发现组织Treg基本为活化和CD69+Treg，包括ST+和KLRG1+群。值得注意的是，这些表型在不同组织间基本无差别。总之，这些数据表明几乎所有组织存在Treg，且在非淋巴非肠道组织Treg表型相似。随后，作者探究性别、年龄和肠道菌群对组织Treg的影响。结果发现Treg表型在雌雄之间几乎无差别，除了雌性唾液腺Treg增加而雄性白色脂肪Treg增加；而组织Treg在老龄小鼠中增加5-20倍，增加最多的是白色脂肪组织和肝脏。除了白色脂肪组织和肌肉，Treg占CD4+T细胞的比例基本稳定，表明Treg的增加可能是由于整体CD4+T细胞的炎性扩增；除了骨髓和肠道粘膜固有层趋势相反，大部分组织Treg随肠道菌群复杂性增加而增加。Treg表型除了ICOS表达随菌群复杂性增加而增加外其余表达稳定。这些数据表明组织Treg数量受年龄和肠道菌群影响，但Treg表型较为稳定。 作者分离各个组织Treg行RNA-seq分析，包括血液、淋巴组织（脾脏、淋巴结和派氏结）、肠相关组织（上皮间白细胞和黏膜固有层）和非淋巴非肠道组织（肝、肺、胰腺和肾）。结果表明肠相关Treg和非淋巴组织Treg在转录组上相似，且各个非淋巴组织Treg也呈现高度相似特征。之后，团队分析组织驻留相关基因，包括CD69、ST2、KLRG1、CD103、Blimp、BATF、CD11a、S1PR2、Areg和HIF1α，对组织Treg的影响。通过WT小鼠和上述基因缺失小鼠构建1：1嵌合小鼠，作者发现除了Blimp和BATF3，其余组织浸润相关基因对组织Treg影响较小，且观察到的差异也是泛组织而非组织特异。这些结果说明组织Treg不仅有统一的表型，同时也分享相同的组织驻留关键分子。这种表型和分子依赖的相似性是由于Treg的多样性被抑制还是组织驻留时间有限？为此，作者构建多时间点的CD45.1-CD45.2 parabiosis模型，结果发现在淋巴组织，CD69+Treg在淋巴结停留3天，脾脏17天、肠系膜淋巴结4周；在非淋巴组织，CD69+Treg平均停留3周，白色脂肪组织则达到8周；肠相关Treg停留时间为7-8周。在平均停留3周后，大多数CD69+Treg离开组织。总之，这些结果表明组织驻留Treg在组织停留时间较短，并支持活化Treg进入-短暂停留-离开的循环迁移模型。 尽管上述数据不支持Treg的长期驻留，但仍可能存在两种情况。1. 克隆限制的循环迁移，即克隆限制Treg在一个组织和淋巴组织之间循环迁移。2. 泛组织迁移模型，即Treg在多个组织循环迁移。作者首先评价组织Treg的TCR克隆性，结果发现非淋巴组织驻留Treg具有高度克隆共享。相反，肠黏膜固有层Treg的TCR在非肠道组织很少观察到。随后，作者挑选组织Treg的TCR并通过编码联合逆转录病毒对造血干细胞进行逆基因再表达并过继入小鼠体内，发现60%逆基因再表达细胞分化为Treg且大部分Treg均遵循泛组织迁移模型，仅少数TCR有组织特异性分布倾向。总之，这些数据支持泛组织Treg迁移驻留模型。 综上所述，这项研究揭示组织间Treg表型和TCR相似且定居时间较短，并提出组织驻留Treg的泛组织迁移模型，为组织驻留Treg的认知提供另一种理解。 模式图（Credit: Immunity） 参考文献 1. Florent, Ginhoux., Martin, Guilliams.(2016). Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity, 44(3), 0. doi:10.1016/j.immuni.2016.02.024 2. Marcus, Buggert., David A, Price., Laura K, Mackay., Michael R, Betts.(2023). Human circulating and tissue-resident memory CD8(+) T cells. Nat Immunol, 24(7), 0. doi:10.1038/s41590-023-01538-6 3. Andrés R, Muñoz-Rojas., Diane, Mathis.(2021). Tissue regulatory T cells: regulatory chameleons. Nat Rev Immunol, 21(9), 0. doi:10.1038/s41577-021-00519-w 4. Markus, Feuerer., Laura, Herrero., Daniela, Cipolletta., Afia, Naaz., Jamie, Wong., Ali, Nayer., Jongsoon, Lee., et al.(2009). Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med, 15(8), 0. doi:10.1038/nm.2002 5. Tianli, Xiao., P Kent, Langston., Andrés R, Muñoz-Rojas., Teshika, Jayewickreme., Mitchell A, Lazar., Christophe, Benoist., Diane, Mathis.(2022). T(regs) in visceral adipose tissue up-regulate circadian-clock expression to promote fitness and enforce a diurnal rhythm of lipolysis. Sci Immunol, 7(75), 0. doi:10.1126/sciimmunol.abl7641 6. Dalia, Burzyn., Wilson, Kuswanto., Dmitriy, Kolodin., Jennifer L, Shadrach., Massimiliano, Cerletti., Young, Jang., Esen, Sefik., Tze Guan, Tan., Amy J, Wagers., Christophe, Benoist., Diane, Mathis.(2013). A special population of regulatory T cells potentiates muscle repair. Cell, 155(6), 0. doi:10.1016/j.cell.2013.10.054 7. Lokesh A, Kalekar., Jarish N, Cohen., Nicolas, Prevel., Priscila Muñoz, Sandoval., Anubhav N, Mathur., et al.(2019). Regulatory T cells in skin are uniquely poised to suppress profibrotic immune responses. Sci Immunol, 4(39), 0. doi:10.1126/sciimmunol.aaw2910 8. Niwa, Ali., Bahar, Zirak., Robert Sanchez, Rodriguez., Mariela L, Pauli., Hong-An, Truong., Kevin, Lai., Richard, et al.(2017). Regulatory T Cells in Skin Facilitate Epithelial Stem Cell Differentiation. Cell, 169(6), 0. doi:10.1016/j.cell.2017.05.002 9. Florez, L.M., Fourcade, G., Darrassse-Je` ze, G., Barennes, P., GanFernandez, K., Re´ gnier, P., Nehar-Belaid, D., et al. (2023). Tissue-resident uterine regulatory T cells support fetal growth. Preprint at bioRxiv. https://doi.org/10.1101/2023.09.07.554921. https://doi.org/10.1016/j.immuni.2024.05.023 责编|探索君 排版|探索君 文章来源|“BioArt” End 往期精选 围观 一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版） 热文 Cell | 是什么决定了细胞的大小？ 热文 Nature | 2024年值得关注的七项技术 热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望 热文 CRISPR技术进化史 | 24年Cell综述

Initiated Single-Ascending Dose (SAD) Phase 1 clinical study evaluating LP659 LA JOLLA, Calif.--(BUSINESS WIRE)-- Longboard Pharmaceuticals, Inc. (Nasdaq: LBPH), a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases, today announced the initiation of a Phase 1 randomized, double-blind, placebo-controlled, SAD clinical study of LP659. LP659 is an oral, centrally acting, next-generation sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5 modulator in development for the potential treatment of rare neuroinflammatory conditions. “Expanding our potentially best-in-class clinical-stage pipeline with LP659 is very exciting. We founded Longboard to leverage Arena’s successful record of discovering and developing molecules with differentiated pharmacokinetics, pharmacodynamics and receptor engagement, which we believe has been validated again by the recent approval of etrasimod, an S1P receptor modulator. LP659 was designed by the same team as etrasimod with the goal of creating a next-generation, brain penetrant S1P receptor modulator while preserving its unique qualities, including avoiding activity at S1P2 and S1P3 receptor subtypes which have been associated with serious adverse events. We plan to share Phase 1 SAD data and additional clinical plans for LP659 in the first half of 2024,” stated Kevin R. Lind, Longboard’s President and Chief Executive Officer. About the Phase 1 SAD Clinical Study The primary objective of this Phase 1 randomized, double-blind, placebo-controlled, single-ascending dose clinical study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of LP659 in up to 48 healthy adult volunteers. About LP659 LP659 is an oral, centrally acting, next-generation S1P receptor subtypes 1 and 5 (S1P1,5) modulator in development for rare neuroinflammatory conditions. Aberrant modulation of the S1P receptor has been shown to be involved in a wide range of neurological diseases. LP659 avoids S1P2,3 which may be associated with off-target adverse events. We believe LP659’s potential selectivity and specificity could result in a superior pro the clinic compared to drugs that may not fully engage the intended GPCR target, may cause off-target activity, or may be associated with other undesirable effects. ABOUT LONGBOARD PHARMACEUTICALS Longboard Pharmaceuticals, Inc. is a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases. Longboard is working to advance a portfolio of centrally acting product candidates designed to be highly selective for specific G protein-coupled receptors (GPCRs). Longboard’s small molecule product candidates are based on more than 20 years of GPCR research. Longboard is evaluating LP352, an oral, centrally acting 5-hydroxytryptamine 2C (5-HT2C) receptor superagonist, with no observed impact on 5-HT2B and 5-HT2A receptor subtypes. LP352 is currently in a Phase 1b/2a clinical trial, the PACIFIC Study, evaluating participants ages 12 to 65 years old with a broad range of Developmental and Epileptic Encephalopathies (DEEs), including Lennox-Gastaut syndrome, Dravet syndrome and other DEEs. Enrollment was completed in the summer of 2023, and topline data are expected in January 2024. Longboard is also evaluating LP659, an oral, centrally acting, next-generation sphingosine-1-phosphate (S1P) receptor subtypes 1 and 5 modulator, which is in development for the potential treatment of rare neuroinflammatory conditions in a Phase 1 single-ascending dose (SAD) clinical trial in healthy volunteers. FORWARD-LOOKING STATEMENTS Certain statements in this press release are forward-looking statements that involve a number of risks and uncertainties. In some cases, you can identify forward-looking statements by words such as “focus”, “in development for”, “potential”, “believe”, “goal”, “plan”, “first half of 2024”, “objective”, “may”, “could”, “working to”, “designed to”, “expect”, “January 2024”, “later this year”, or the negative, plural or other tenses of these words or other comparable language, and they may include, without limitation, statements about the following: the vesting of stock options; continued employment of newly hired Longboard employees; Longboard’s clinical and preclinical product candidates and programs, including their advancement, timing of initiation and completion of clinical trials, timing of topline data from clinical trials, characteristics of clinical trial participants, plans for future clinical trials, their potential (including to be highly selective, have differentiated pharmacokinetics, pharmacodynamics and receptor engagement, have unique qualities associated with other compounds, have a superior profile, and the numbers and types of conditions they may address), and their design and characteristics; Longboard’s ability to develop product candidates and deliver medicines; and Longboard’s focus and work. For such statements, Longboard claims the protection of the Private Securities Litigation Reform Act of 1995. Actual events or results may differ materially from Longboard’s expectations. Factors that could cause actual results to differ materially from those stated or implied by Longboard’s forward-looking statements include, but are not limited to, the following: risks related to Longboard’s limited operating history, financial position and need for additional capital; Longboard will need additional managerial and financial resources to advance all of its programs, and you and others may not agree with the manner Longboard allocates its resources; risks related to the development and commercialization of Longboard’s product candidates; Longboard’s product candidates are in the early phases of a lengthy research and development process, the timing, manner and outcome of research, development and regulatory review is uncertain, and Longboard’s product candidates may not advance in research or development or be approved for marketing; enrolling participants in Longboard’s ongoing and intended clinical trials is competitive and challenging; PACIFIC Study participants’ diagnoses are as of time of screening and are subject to change; macroeconomic events stemming from the COVID-19 pandemic or evolving geopolitical developments such as the conflicts in Ukraine and the Middle East, including but not limited to the impact on Longboard’s clinical trials and operations, the operations of Longboard’s suppliers, partners, collaborators, and licensees, and capital markets, which in each case remains uncertain; risks related to unexpected or unfavorable new data; nonclinical and clinical data is voluminous and detailed, and regulatory agencies may interpret or weigh the importance of data differently and reach different conclusions than Longboard or others, request additional information, have additional recommendations or change their guidance or requirements before or after approval; results of clinical trials and other studies are subject to different interpretations and may not be predictive of future results; topline data may not accurately reflect the complete results of a particular study or trial; risks related to relying on licenses or collaborative arrangements; other risks related to Longboard’s dependence on third parties; competition; product liability or other litigation or disagreements with others; government and third-party payor actions, including relating to reimbursement and pricing; risks related to regulatory compliance; and risks related to Longboard’s and third parties’ intellectual property rights. Additional factors that could cause actual results to differ materially from those stated or implied by Longboard’s forward-looking statements are disclosed in Longboard’s filings with the Securities and Exchange Commission (SEC). These forward-looking statements represent Longboard’s judgment as of the time of this release. Longboard disclaims any intent or obligation to update these forward-looking statements, other than as may be required under applicable law.