Basic-leucine zipper transcription factor ATF-like (BATF) and interferon regulatory factor 4 (IRF4) are crucial transcription factors for generation of cytotoxic effector and memory CD8+ T cells. JunB is required for expression of genes controlled by BATF and IRF4 in CD4+ T cell responses, but the role of JunB in CD8+ T cells remains unknown. Here, we demonstrate that JunB is essential for cytotoxic CD8+ T cell responses. JunB expression is transiently induced, depending on T cell receptor (TCR) signal strength. JunB deficiency severely impairs clonal expansion of effector CD8+ T cells in response to acute infection with Listeria monocytogenes. Junb-deficient CD8+ T cells fail to control transcription and chromatin accessibility of a specific set of genes regulated by BATF and IRF4, resulting in impaired cell survival, glycolysis, and cytotoxic CD8+ T cell differentiation. Furthermore, JunB deficiency enhances expression of coinhibitory receptors, including programmed death receptor 1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM3) upon activation of naïve CD8+ T cells. These results indicate that JunB, in collaboration with BATF and IRF4, promotes multiple key events in the early stage of cytotoxic CD8+ T cell responses.
碱性亮氨酸拉链转录因子 ATF 样(BATF)和干扰素调节因子 4(IRF4)是产生细胞毒性效应细胞和记忆 CD8+ T 细胞的关键转录因子。在 CD4+ T 细胞反应中,由 BATF 和 IRF4 控制的基因的表达需要 JunB,但 JunB 在 CD8+ T 细胞中的作用仍然未知。在这里,我们证明了 JunB 对于细胞毒性 CD8+ T 细胞反应至关重要。JunB的表达是瞬时诱导的,取决于T细胞受体(TCR)的信号强度。在李斯特菌急性感染时,缺乏JunB会严重影响效应CD8+ T细胞的克隆扩增。Junb缺陷的CD8+ T细胞无法控制由BATF和IRF4调控的一组特定基因的转录和染色质可及性,导致细胞存活、糖酵解和细胞毒性CD8+ T细胞分化受损。此外,在激活幼稚 CD8+ T 细胞时,缺乏 JunB 会增强共抑制受体的表达,包括程序性死亡受体 1(PD-1)和 T 细胞免疫球蛋白粘蛋白-3(TIM3)。这些结果表明,JunB 与 BATF 和 IRF4 合作,促进了细胞毒性 CD8+ T 细胞反应早期的多个关键事件。
{"title":"JunB is required for CD8+ T cell responses to acute infections.","authors":"Shukla Sarkar, Naoyuki Taira, Tsung-Han Hsieh, Hsiao-Chiao Chien, Masato Hirota, Shin-Ichi Koizumi, Daiki Sasaki, Miho Tamai, Yu Seto, Mio Miyagi, Hiroki Ishikawa","doi":"10.1093/intimm/dxae063","DOIUrl":"https://doi.org/10.1093/intimm/dxae063","url":null,"abstract":"<p><p>Basic-leucine zipper transcription factor ATF-like (BATF) and interferon regulatory factor 4 (IRF4) are crucial transcription factors for generation of cytotoxic effector and memory CD8+ T cells. JunB is required for expression of genes controlled by BATF and IRF4 in CD4+ T cell responses, but the role of JunB in CD8+ T cells remains unknown. Here, we demonstrate that JunB is essential for cytotoxic CD8+ T cell responses. JunB expression is transiently induced, depending on T cell receptor (TCR) signal strength. JunB deficiency severely impairs clonal expansion of effector CD8+ T cells in response to acute infection with Listeria monocytogenes. Junb-deficient CD8+ T cells fail to control transcription and chromatin accessibility of a specific set of genes regulated by BATF and IRF4, resulting in impaired cell survival, glycolysis, and cytotoxic CD8+ T cell differentiation. Furthermore, JunB deficiency enhances expression of coinhibitory receptors, including programmed death receptor 1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM3) upon activation of naïve CD8+ T cells. These results indicate that JunB, in collaboration with BATF and IRF4, promotes multiple key events in the early stage of cytotoxic CD8+ T cell responses.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bruno Marques Vieira, Beatriz Fernandes Almeida, Marcelo Pelajo Machado
The milky spots are structures found in the omentum of humans and other vertebrates, representing a fraction of the lymphomyeloid tissue associated with the celom. They majorly consist of B lymphocytes, T lymphocytes, and macrophages. Also found in smaller quantities are mesothelial, stromal, dendritic, and rare mast cells. In an experimental model of Schistosoma mansoni infection, there is significant activation of the omentum and milky spots, which exhibit numerous eosinophils. Despite being described for many years, the complete profile of cells found in milky spots and their functions remains largely unexplored. Here, we evaluate the leukocyte populations of the milky spots in homeostasis and a murine model of Schistosoma mansoni infection. The histopathological characterizations, phenotypic profile analysis, and characterization of the eosinophilic potential of progenitors and precursors comparing the milky spots with the spleen and bone marrow showed significant activation of milky spots in infected mice, with changes in the profile over the analyzed times, showing signs of migration and activation of eosinophils, with local eosinopoiesis and maintenance of the eosinophilic population. In naive mice, B1a and B1b cells comprise only a small fraction of B lymphocytes. However, B1b cells expand significantly during infection, peaking at 60 DPI before stabilizing by 90 DPI. B1a cells also increase initially but decrease over time. The behavior of milky spots differs from other primary and secondary lymphoid organs, acting as a central lymphoid organ in cavity immunity.
乳斑是在人类和其他脊椎动物的网膜中发现的结构,是与腹腔相关的淋巴细胞组织的一部分。它们主要由 B 淋巴细胞、T 淋巴细胞和巨噬细胞组成。此外,还有少量间皮细胞、基质细胞、树突状细胞和罕见的肥大细胞。在曼氏血吸虫感染的实验模型中,网膜和乳斑被明显激活,出现大量嗜酸性粒细胞。尽管嗜酸性粒细胞已被描述多年,但乳斑中发现的细胞的完整特征及其功能在很大程度上仍未被探索。在这里,我们评估了乳斑中白细胞群的平衡状态以及曼氏血吸虫感染的小鼠模型。组织病理学特征、表型轮廓分析以及嗜酸性粒细胞祖细胞和前体细胞的嗜酸性粒细胞潜能特征显示,嗜酸性粒细胞祖细胞和前体细胞与脾脏和骨髓进行比较后发现,在感染小鼠体内,嗜酸性粒细胞乳斑显著活化,其轮廓在分析时间内发生了变化,显示出嗜酸性粒细胞迁移和活化的迹象,并伴有局部嗜酸性粒细胞生成和嗜酸性粒细胞群的维持。在幼稚小鼠体内,B1a 和 B1b 细胞只占 B 淋巴细胞的一小部分。然而,B1b 细胞在感染期间会显著增大,在 60 DPI 时达到峰值,到 90 DPI 时趋于稳定。B1a 细胞最初也会增加,但随着时间的推移会减少。乳斑的表现不同于其他初级和次级淋巴器官,它是空腔免疫的核心淋巴器官。
{"title":"Eosinophil and B cell dynamics in the milky spots from Schistosoma mansoni-infected mice - Comparison with spleen and bone marrow, and extramedullary eosinopoiesis.","authors":"Bruno Marques Vieira, Beatriz Fernandes Almeida, Marcelo Pelajo Machado","doi":"10.1093/intimm/dxae064","DOIUrl":"https://doi.org/10.1093/intimm/dxae064","url":null,"abstract":"<p><p>The milky spots are structures found in the omentum of humans and other vertebrates, representing a fraction of the lymphomyeloid tissue associated with the celom. They majorly consist of B lymphocytes, T lymphocytes, and macrophages. Also found in smaller quantities are mesothelial, stromal, dendritic, and rare mast cells. In an experimental model of Schistosoma mansoni infection, there is significant activation of the omentum and milky spots, which exhibit numerous eosinophils. Despite being described for many years, the complete profile of cells found in milky spots and their functions remains largely unexplored. Here, we evaluate the leukocyte populations of the milky spots in homeostasis and a murine model of Schistosoma mansoni infection. The histopathological characterizations, phenotypic profile analysis, and characterization of the eosinophilic potential of progenitors and precursors comparing the milky spots with the spleen and bone marrow showed significant activation of milky spots in infected mice, with changes in the profile over the analyzed times, showing signs of migration and activation of eosinophils, with local eosinopoiesis and maintenance of the eosinophilic population. In naive mice, B1a and B1b cells comprise only a small fraction of B lymphocytes. However, B1b cells expand significantly during infection, peaking at 60 DPI before stabilizing by 90 DPI. B1a cells also increase initially but decrease over time. The behavior of milky spots differs from other primary and secondary lymphoid organs, acting as a central lymphoid organ in cavity immunity.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The transcription factor T-bet is essential for the anti-tumor effector function of NK cells, but the mechanism regulating its expression in NK cells remains unclear. In this study, we aimed to identify an NK cell intrinsic regulator that controls T-bet expression. Using T-bet-luciferase reporter assay screening, we identified a protein phosphatase inhibitor as a potential activator of T-bet expression. A series of PP2A-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expressions of T-bet and its downstream effector molecules, granzyme B and IFN-γ, were also upregulated in NK cells. Mechanistically, PP2Ai increased the phosphorylation of mTOR and ribosomal protein S6 in NK cells, and mTOR inhibitor canceled the effects of PP2Ai in NK cells. Importantly, NK cells isolated from PP2Ai-treated mice showed higher cytotoxicity and IFN-γ production; therefore, they increased the anti-tumor effector function of NK cells. Accordingly, PP2Ai treatment inhibited lung metastasis of B16 melanoma by NK cell- and mTOR-dependent mechanisms. These results suggest that PP2A negatively regulates NK cell T-bet expression and effector function by an mTOR-dependent mechanism.
转录因子 T-bet 对 NK 细胞的抗肿瘤效应功能至关重要,但其在 NK 细胞中的表达调控机制仍不清楚。在这项研究中,我们的目的是找出一种控制T-bet表达的NK细胞内在调节因子。通过T-bet-荧光素酶报告实验筛选,我们发现一种蛋白磷酸酶抑制剂是T-bet表达的潜在激活剂。一系列 PP2A 特异性抑制剂(PP2Ai)或 PP2A siRNA 诱导了 T-bet 的表达。在 PP2Ai 处理的小鼠中,T-bet 及其下游效应分子颗粒酶 B 和 IFN-γ 在 NK 细胞中的表达也上调。从机理上讲,PP2Ai增加了NK细胞中mTOR和核糖体蛋白S6的磷酸化,而mTOR抑制剂消除了PP2Ai对NK细胞的影响。重要的是,从经 PP2Ai 处理的小鼠体内分离出的 NK 细胞显示出更高的细胞毒性和 IFN-γ 生成,因此增强了 NK 细胞的抗肿瘤效应功能。因此,PP2Ai通过NK细胞和mTOR依赖机制抑制了B16黑色素瘤的肺转移。这些结果表明,PP2A通过mTOR依赖性机制负向调节NK细胞T-bet的表达和效应功能。
{"title":"PP2A negatively regulates NK cell T-bet expression and anti-tumor effector function.","authors":"Yui Shinzawa, Daisuke Hara, Yuki Shinguryo, Satoru Yokoyama, Manabu Kawada, Yoshihiro Hayakawa","doi":"10.1093/intimm/dxae057","DOIUrl":"https://doi.org/10.1093/intimm/dxae057","url":null,"abstract":"<p><p>The transcription factor T-bet is essential for the anti-tumor effector function of NK cells, but the mechanism regulating its expression in NK cells remains unclear. In this study, we aimed to identify an NK cell intrinsic regulator that controls T-bet expression. Using T-bet-luciferase reporter assay screening, we identified a protein phosphatase inhibitor as a potential activator of T-bet expression. A series of PP2A-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expressions of T-bet and its downstream effector molecules, granzyme B and IFN-γ, were also upregulated in NK cells. Mechanistically, PP2Ai increased the phosphorylation of mTOR and ribosomal protein S6 in NK cells, and mTOR inhibitor canceled the effects of PP2Ai in NK cells. Importantly, NK cells isolated from PP2Ai-treated mice showed higher cytotoxicity and IFN-γ production; therefore, they increased the anti-tumor effector function of NK cells. Accordingly, PP2Ai treatment inhibited lung metastasis of B16 melanoma by NK cell- and mTOR-dependent mechanisms. These results suggest that PP2A negatively regulates NK cell T-bet expression and effector function by an mTOR-dependent mechanism.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Onco-immunotherapy via blocking checkpoint-inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to immunosuppressive and poorly immunogenic "cold" tumor microenvironment (TME). Turning up the heat of such cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene- I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5) along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1) during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs, but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cells apoptosis, immunomodulation, and inducing phagocytic "eat me" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming "cold" TME into immunogenic "hot" TME of PCa.
{"title":"Intra-tumoral delivery of 5'ppp-dsRNA induces robust anti-tumor response via RIG-I activation and Bcl-2 gene downregulation in murine model of prostate cancer.","authors":"Kasturi Ganguly, Siddhanath M Metkari, Barnali Biswas, Rambhadur Subedi, Taruna Madan","doi":"10.1093/intimm/dxae061","DOIUrl":"https://doi.org/10.1093/intimm/dxae061","url":null,"abstract":"<p><p>Onco-immunotherapy via blocking checkpoint-inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to immunosuppressive and poorly immunogenic \"cold\" tumor microenvironment (TME). Turning up the heat of such cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene- I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5) along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1) during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs, but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cells apoptosis, immunomodulation, and inducing phagocytic \"eat me\" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming \"cold\" TME into immunogenic \"hot\" TME of PCa.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.
CD26 是一种人类 T 细胞共振分子,也是一种 T 细胞亚群标志物,在多种自身免疫性疾病中都有 CD26+ T 细胞在炎症组织和外周血中增加的报道。相比之下,我们的研究小组以前曾发现,系统性红斑狼疮(SLE)患者的循环 CD26+ T 细胞水平降低,但 CD26 T 细胞表面表达减少在系统性红斑狼疮病理学中的作用仍有待阐明。在本研究中,我们利用 57 名系统性红斑狼疮患者和 31 名健康成年志愿者的外周血单核细胞进行了基于 CD26 的 T 细胞亚群分析。我们发现,CD26(-)T 细胞群的增加反映了系统性红斑狼疮患者 CD8 T 细胞和 CD4 T 细胞中 CD26(-)CD28(-)细胞毒性亚群的异常扩张。对CD26(-)CD28(-) CD4和CD8 T细胞群的单细胞RNA测序分析表明,它们具有与自然杀伤T细胞相似的独特特征。此外,在一些有肾脏表现的活动期系统性红斑狼疮患者中,CD26(-)CD28(-)T细胞的水平会升高。同时,泼尼松龙治疗对这些细胞群的影响因人而异,在一些非活动期系统性红斑狼疮患者中,这些细胞毒性效应细胞群的水平仍然升高。总之,我们的数据表明,对系统性红斑狼疮患者的这些细胞毒效应群进行分析,可能是对这一明显异质性疾病进行分类的有用工具。
{"title":"An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus.","authors":"Ryo Hatano, Hayato Nakamura, Ayako Yamamoto, Haruna Otsuka, Takumi Itoh, Nao Hosokawa, Jinghui Yu, Sedigheh Ranjbar, Yuta Hasegawa, Tsutomu Sato, Nam H Dang, Kei Ohnuma, Shinji Morimoto, Iwao Sekigawa, Tomonori Ishii, Chikao Morimoto","doi":"10.1093/intimm/dxae062","DOIUrl":"https://doi.org/10.1093/intimm/dxae062","url":null,"abstract":"<p><p>CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ PD-1+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant proinflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions including autoimmunity and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, autoimmune and chronic inflammatory diseases and provides a novel therapeutic clue.
免疫系统中与年龄有关的变化被称为免疫衰老,这种变化似乎具有相当矛盾的表现,即适应性免疫能力减弱,慢性炎症倾向增加,往往伴有自身免疫,这可能是随着年龄增长出现各种疾病的原因。免疫增强表型与 T 系和 B 系独特淋巴细胞亚群的出现有关。我们报告说,在衰老的小鼠中,一个对 T 细胞受体(TCR)反应性严重减弱的 CD153+ PD-1+ CD4+ T 细胞亚群(称为衰老相关 T 细胞(SAT))与潜在的自反应性 CD30+ B 细胞(如自发生殖中心 B 细胞和年龄相关 B 细胞)共同进化。SAT 细胞和 CD30+ B 细胞借助 CD153 与 CD30 的反式相互作用和与 TCR 复合物的顺式相互作用相互激活,导致 TCR 介导的增殖恢复,SAT 细胞分泌大量促炎细胞因子,CD30+ B 细胞激活并产生自身抗体。除正常衰老外,在慢性炎症(包括自身免疫)条件下,SAT 细胞和对应的 B 细胞可能会在淋巴或淋巴外器官的相关组织中加速发育和积累,并可能导致疾病的发病机制和恶化。这篇综述总结并讨论了在免疫增强表型、自身免疫和慢性炎症疾病背景下了解 SAT 细胞的最新进展,并提供了一条新的治疗线索。
{"title":"Senescence-Associated T cells in Immunosenescence and Diseases.","authors":"Yuji Fukushima, Ryuji Ueno, Nagahiro Minato, Masakazu Hattori","doi":"10.1093/intimm/dxae056","DOIUrl":"https://doi.org/10.1093/intimm/dxae056","url":null,"abstract":"<p><p>Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ PD-1+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant proinflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions including autoimmunity and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, autoimmune and chronic inflammatory diseases and provides a novel therapeutic clue.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142346132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called 'atopy') and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred as the 'atopic march' (AM). Clinical, genetic and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM, to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.
特应性疾病,包括特应性皮炎(AD)、食物过敏(FA)、哮喘和过敏性鼻炎(AR)与涉及不同身体部位(即皮肤、气道和消化道)的炎症性疾病密切相关,其特征包括对过敏原的特异性 IgE(所谓的 "特应性")和 Th2 细胞介导的炎症。人们已经认识到,渐冻人症往往先于其他特应性疾病的发生。从婴儿期的过敏性鼻炎发展到儿童后期的过敏性鼻炎或哮喘/过敏性鼻炎被称为 "特应性进展"(AM)。临床、遗传和实验研究已经提供了证据,证明通过 AD 皮肤发生的过敏原致敏可能是特应性哮喘的起源。在此,我们对皮肤在特应性哮喘中的作用进行了最新综述,从与 AD 和特应性哮喘中表皮屏障功能障碍相关的基因突变和环境因素,到皮肤过敏的免疫学机制,特别是最近在研究 AD 期间表皮角质形成细胞或浸润皮肤的免疫细胞产生的关键细胞因子的功能方面取得的进展。我们还强调了制定针对 AD 皮肤的策略以预防和减轻 AM 的重要性。
{"title":"The role of the skin in the atopic march.","authors":"Xin Tang,Mei Li","doi":"10.1093/intimm/dxae053","DOIUrl":"https://doi.org/10.1093/intimm/dxae053","url":null,"abstract":"Atopic diseases, including atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR) are closely related to inflammatory diseases involving different body sites (i.e. the skin, airway, and digestive tract) with characteristic features including specific IgE to allergens (so-called 'atopy') and Th2 cell-mediated inflammation. It has been recognized that AD often precedes the development of other atopic diseases. The progression from AD during infancy to FA or asthma/AR in later childhood is referred as the 'atopic march' (AM). Clinical, genetic and experimental studies have provided evidence that allergen sensitization occurring through AD skin could be the origin of the AM. Here, we provide an updated review focusing on the role of the skin in the AM, from genetic mutations and environmental factors associated with epidermal barrier dysfunction in AD and the AM, to immunological mechanisms for skin sensitization, particularly recent progress on the function of key cytokines produced by epidermal keratinocytes or by immune cells infiltrating the skin during AD. We also highlight the importance of developing strategies that target AD skin to prevent and attenuate the AM.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":"16 1","pages":""},"PeriodicalIF":4.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142267918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.
{"title":"Regnase-1 D141N mutation induces CD4+ T cell-mediated lung granuloma formation via upregulation of Pim2.","authors":"Thin Sandi Htun, Hiroki Tanaka, Shailendra Kumar Singh, Diego Diez, Shizuo Akira","doi":"10.1093/intimm/dxae026","DOIUrl":"10.1093/intimm/dxae026","url":null,"abstract":"<p><p>Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"497-516"},"PeriodicalIF":4.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140862153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chisato Ono, Yuta Kochi, Yoshihiro Baba, Shinya Tanaka
B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.
B细胞的初始活性是通过B细胞中表达的调控分子介导的激活和抑制的平衡来调节的;然而,这一过程的分子机制仍不完全清楚。在这项研究中,我们研究了 Fc 受体样(Fcrl)家族分子 Fcrl5 在体液免疫反应中的功能。我们的研究表明,B细胞特异性过表达Fcrl5能增强T细胞依赖型1(TI1)和T细胞依赖型(TD)反应中抗体(Ab)的产生。此外,在 TD 反应的竞争条件下,它还能促进效应 B 细胞的形成。从机理上讲,体外激动性 Abs 与 Fcrl5 连接可减少细胞死亡,并增强脂多糖(LPS)刺激下 B 细胞的增殖。在抗CD40 Abs和IL-5存在的情况下,Fcrl5结扎不仅能抑制细胞死亡,还能促进分化成浆细胞。这些发现揭示了 Fcrl5 在通过增强 B 细胞活力和浆细胞分化促进体液免疫反应中的新作用。
{"title":"Humoral responses are enhanced by facilitating B cell viability by Fcrl5 overexpression in B cells.","authors":"Chisato Ono, Yuta Kochi, Yoshihiro Baba, Shinya Tanaka","doi":"10.1093/intimm/dxae028","DOIUrl":"10.1093/intimm/dxae028","url":null,"abstract":"<p><p>B cell initial activity is regulated through a balance of activation and suppression mediated by regulatory molecules expressed in B cells; however, the molecular mechanisms underlying this process remain incompletely understood. In this study, we investigated the function of the Fc receptor-like (Fcrl) family molecule Fcrl5, which is constitutively expressed in naive B cells, in humoral immune responses. Our study demonstrated that B cell-specific overexpression of Fcrl5 enhanced antibody (Ab) production in both T cell-independent type 1 (TI1) and T cell-dependent (TD) responses. Additionally, it promoted effector B cell formation under competitive conditions in TD responses. Mechanistically, in vitro ligation of Fcrl5 by agonistic Abs reduced cell death and enhanced proliferation in lipopolysaccharide-stimulated B cells. In the presence of anti-CD40 Abs and IL-5, the Fcrl5 ligation not only suppressed cell death but also enhanced differentiation into plasma cells. These findings reveal a novel role of Fcrl5 in promoting humoral immune responses by enhancing B cell viability and plasma cell differentiation.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"529-540"},"PeriodicalIF":4.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140912210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.
{"title":"Lipid metabolism: a central modulator of RORγt-mediated Th17 cell differentiation.","authors":"Toshio Kanno, Keisuke Miyako, Yusuke Endo","doi":"10.1093/intimm/dxae031","DOIUrl":"10.1093/intimm/dxae031","url":null,"abstract":"<p><p>Among the T helper cell subsets, Th17 cells contribute to the development of various inflammatory and autoimmune diseases, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, steroid-resistant asthma, and multiple sclerosis. Retinoid-related orphan receptor gamma t (RORγt), a nuclear hormone receptor, serves as a master transcription factor for Th17 cell differentiation. Recent findings have shown that modulating the metabolic pathway is critical for Th17 cell differentiation, particularly through the engagement of de novo lipid biosynthesis. Suppression of lipid biosynthesis, either through the pharmacological inhibition or gene deletion of related enzymes in CD4+ T cells, results in significant impairment of Th17 cell differentiation. Mechanistic studies indicate that metabolic fluxes through both the fatty acid and cholesterol biosynthetic pathways have a pivotal role in the regulation of RORγt activity through the generation of endogenous RORγt lipid ligands. This review discusses recent discoveries highlighting the importance of lipid metabolism in Th17 cell differentiation and function, as well as exploring specific molecular pathways involved in RORγt activation through cellular lipid metabolism. We further elaborate on a pioneering therapeutic approach to improve inflammatory and autoimmune disorders via the inhibition of RORγt.</p>","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"487-496"},"PeriodicalIF":4.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}