International immunology最新文献_第3页

Mechanisms and effects of activation of innate immunity by mitochondrial nucleic acids. 线粒体核酸激活先天性免疫的机制和影响

IF 4.8 4区医学

International immunology Pub Date : 2025-02-04 DOI: 10.1093/intimm/dxae052

Prashant Rai, Michael B Fessler

{"title":"Mechanisms and effects of activation of innate immunity by mitochondrial nucleic acids.","authors":"Prashant Rai, Michael B Fessler","doi":"10.1093/intimm/dxae052","DOIUrl":"10.1093/intimm/dxae052","url":null,"abstract":"In recent years, a growing number of roles have been identified for mitochondria in innate immunity. One principal mechanism is that the translocation of mitochondrial nucleic acid species from the mitochondrial matrix to the cytosol and endolysosomal lumen in response to an array of microbial and non-microbial environmental stressors has been found to serve as a second messenger event in the cell signaling of the innate immune response. Thus, mitochondrial DNA and RNA have been shown to access the cytosol through several regulated mechanisms involving remodeling of the mitochondrial inner and outer membranes and to access lysosomes via vesicular transport, thereby activating cytosolic [e.g. cyclic GMP-AMP synthase (cGAS), retinoic acid-inducible gene I (RIG-I)-like receptors], and endolysosomal (Toll-like receptor 7, 9) nucleic acid receptors that induce type I interferons and pro-inflammatory cytokines. In this mini-review, we discuss these molecular mechanisms of mitochondrial nucleic acid mislocalization and their roles in host defense, autoimmunity, and auto-inflammatory disorders. The emergent paradigm is one in which host-derived DNA interestingly serves as a signal amplifier in the innate immune response and also as an alarm signal for disturbances in organellar homeostasis. The apparent vast excess of mitochondria and mitochondrial DNA nucleoids per cell may thus serve to sensitize the cell response to stressors while ensuring an underlying reserve of intact mitochondria to sustain cellular metabolism. An improved understanding of these molecular mechanisms will hopefully afford future opportunities for therapeutic intervention in human disease.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"133-142"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142107087","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}

引用次数: 0

An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus. 系统性红斑狼疮患者 CD26（-）CD28（-）细胞毒性效应 CD4 和 CD8 T 细胞群异常增加。

IF 4.8 4区医学

International immunology Pub Date : 2025-02-04 DOI: 10.1093/intimm/dxae062

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

{"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":"10.1093/intimm/dxae062","url":null,"abstract":"CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and the 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 the 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, the 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.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"153-172"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","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}

引用次数: 0

Senescence-associated T cells in immunosenescence and diseases. 免疫衰老和疾病中的衰老相关 T 细胞。

IF 4.8 4区医学

International immunology Pub Date : 2025-02-04 DOI: 10.1093/intimm/dxae056

Yuji Fukushima, Ryuji Ueno, Nagahiro Minato, Masakazu Hattori

{"title":"Senescence-associated T cells in immunosenescence and diseases.","authors":"Yuji Fukushima, Ryuji Ueno, Nagahiro Minato, Masakazu Hattori","doi":"10.1093/intimm/dxae056","DOIUrl":"10.1093/intimm/dxae056","url":null,"abstract":"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+ programmed cell death protein 1 (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 pro-inflammatory 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, as well as autoimmune and chronic inflammatory diseases, and it provides a novel therapeutic clue.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"143-152"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","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}

引用次数: 0

Eosinophil and B-cell dynamics in the milky spots from Schistosoma mansoni-infected mice: comparison with spleen and bone marrow, and extramedullary eosinopoiesis. 曼氏血吸虫感染小鼠乳斑中的嗜酸性粒细胞和 B 细胞动态--与脾脏和骨髓以及髓外嗜酸性粒细胞生成的比较。

IF 4.8 4区医学

International immunology Pub Date : 2025-02-04 DOI: 10.1093/intimm/dxae064

Bruno Marques Vieira, Beatriz Fernandes Almeida, Marcelo Pelajo Machado

{"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":"10.1093/intimm/dxae064","url":null,"abstract":"The milky spots (MS) 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 MS, which exhibit numerous eosinophils. Despite being described for many years, the complete profile of cells found in MS and their functions remains largely unexplored. Here, we evaluate the leukocyte populations of the MS in homeostasis and a murine model of S. mansoni infection. The histopathological characterization, phenotypic profile analysis, and characterization of the eosinophilic potential of progenitors and precursors comparing the MS with the spleen and bone marrow showed significant activation of MS 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 make up only a small fraction of B lymphocytes. However, B1b cells expand significantly during infection, peaking at 60 days post-infection (DPI) before stabilizing by 90 DPI. B1a cells also increase initially but decrease over time. The behavior of MS differs from other primary and secondary lymphoid organs, acting as a central lymphoid organ in cavity immunity.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"173-185"},"PeriodicalIF":4.8,"publicationDate":"2025-02-04","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}

引用次数: 0

CD20 and CD19 promote proliferation driven by the IgM-TLR9-L265P MyD88 complex. CD20和CD19促进IgM-TLR9-L265P MyD88复合体驱动的增殖。

IF 4.8 4区医学

International immunology Pub Date : 2025-01-27 DOI: 10.1093/intimm/dxaf004

Yohei Kobayashi, Ryota Sato, Yuri Shimizu, Ryutaro Fukui, Takuma Shibata, Hiroki Tsukamoto, Takeshi Tsubata, Kensuke Miyake

{"title":"CD20 and CD19 promote proliferation driven by the IgM-TLR9-L265P MyD88 complex.","authors":"Yohei Kobayashi, Ryota Sato, Yuri Shimizu, Ryutaro Fukui, Takuma Shibata, Hiroki Tsukamoto, Takeshi Tsubata, Kensuke Miyake","doi":"10.1093/intimm/dxaf004","DOIUrl":"https://doi.org/10.1093/intimm/dxaf004","url":null,"abstract":"The cancer driver mutation L265P MyD88 is found in approximately 30 % of cases in the activated B cell-like subgroup of diffuse large B cell-like lymphoma (ABC DLBCL). L265P MyD88 forms a complex with TLR9 and IgM, referred to as the My-T-BCR complex, to drive proliferation. We here show that the B cell surface molecules CD19 and CD20 enhance proliferation mediated by the My-T-BCR complex. Using the IL-3-dependent Ba/F3 line transduced to express the IgM complex (IgM, CD79a, and CD79b) and TLR9, we observed proliferation in the presence of anti-IgM antibody and the TLR9 ligand CpG-B. TLR9 was constitutively associated with IgM and L252P MyD88. CD19 promoted proliferation with anti-IgM and CpG-B specifically in L252P MyD88-expressing Ba/F3 cells, while CD20 enhanced the proliferation in both wild-type- and L252P MyD88-expressing Ba/F3 cells. Additionally, CD20 uniquely enabled IgM-mediated proliferation in L252P MyD88-expressing Ba/F3 cells. Although CpG-B was not required for this proliferation, TLR9 expression remained indispensable. In the ABC DLBCL line TMD8, anti-IgM Ab mediated growth was impaired by the lack of CD20 and CD19 or of TLR9. Mechanistically, CD19 promoted IgM-dependent AKT phosphorylation, whereas CD20 increased expression of cell surface IgM, thereby enhancing the formation of the IgM-TLR9 complex. These findings suggest that CD19 and CD20 differentially contribute to the proliferation driven by the My-T-BCR complex.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046621","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}

引用次数: 0

TLR7 responses in glomerular macrophages accelerate the progression of glomerulonephritis in NZBWF1 mice. TLR7在肾小球巨噬细胞中的应答加速了NZBWF1小鼠肾小球肾炎的进展。

IF 4.8 4区医学

International immunology Pub Date : 2025-01-27 DOI: 10.1093/intimm/dxaf005

Reika Tanaka, Yusuke Murakami, Dorothy Ellis, Jun Seita, Wu Yinga, Shigeru Kakuta, Keiki Kumano, Ryutaro Fukui, Kensuke Miyake

{"title":"TLR7 responses in glomerular macrophages accelerate the progression of glomerulonephritis in NZBWF1 mice.","authors":"Reika Tanaka, Yusuke Murakami, Dorothy Ellis, Jun Seita, Wu Yinga, Shigeru Kakuta, Keiki Kumano, Ryutaro Fukui, Kensuke Miyake","doi":"10.1093/intimm/dxaf005","DOIUrl":"https://doi.org/10.1093/intimm/dxaf005","url":null,"abstract":"Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies and damage to multiple organs. Glomerulonephritis, a manifestation involving glomerular deposition of immune complexes and complement components, significantly contributes to disease morbidity. Although the endosomal single-stranded RNA sensor TLR7 is known to drive glomerulonephritis by promoting autoantibody production in B cells, the contribution of macrophage TLR7 responses to glomerulonephritis remains poorly understood. Here, we have examined Tlr7‒/‒ NZBWF1 mice and found that TLR7-deficiency ameliorates lupus nephritis by abolishing autoantibody production against RNA-associated antigens, C3 deposition, and macrophage accumulation in glomeruli. Furthermore, TLR7 signaling increased CD31 expression on glomerular endothelial cells and Ly6Clow macrophages but not on T and B cells, suggesting that CD31 mediates TLR7-dependent migration of monocyte into glomeruli. Compared to their splenic counterparts, glomerular macrophages produced IL-1β in a TLR7-dependent manner. In addition, single cell RNA sequencing (scRNA-seq) of glomerular macrophages revealed that TLR7 signaling induced expression of lupus associated genes including those encoding Chitinase 3 like 1, ferritin heavy chain 1, IKKε, and complement factor B (CfB). Although serum CfB did not increase in NZBWF1 mice, TLR7-dependent CfB protein expression was detected in glomerular macrophages. In addition, TLR7 signaling promoted C3 cleavage and deposition predominantly on mesangial cells. These findings suggest that TLR7 responses in glomerular macrophages accelerates the progression of glomerulonephritis in NZBWF1 mice.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046626","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}

引用次数: 0

Beneficial effects on T cells by photodynamic therapy with talaporfin enhance cancer immunotherapy. talaporfin光动力治疗对T细胞的有益作用增强了癌症免疫治疗。

IF 4.8 4区医学

International immunology Pub Date : 2025-01-22 DOI: 10.1093/intimm/dxaf003

Ehab M Ezzaldeen, Tomonori Yaguchi, Ryotaro Imagawa, Mohamed A Soltan, Akira Hirata, Kosaku Murakami, Hirotake Tsukamoto, Manabu Muto, Tasuku Honjo, Kenji Chamoto

{"title":"Beneficial effects on T cells by photodynamic therapy with talaporfin enhance cancer immunotherapy.","authors":"Ehab M Ezzaldeen, Tomonori Yaguchi, Ryotaro Imagawa, Mohamed A Soltan, Akira Hirata, Kosaku Murakami, Hirotake Tsukamoto, Manabu Muto, Tasuku Honjo, Kenji Chamoto","doi":"10.1093/intimm/dxaf003","DOIUrl":"https://doi.org/10.1093/intimm/dxaf003","url":null,"abstract":"Photodynamic therapy (PDT), a local cancer treatment using photosensitizers, has been reported to enhance antitumor immune responses by inducing immunogenic cell death. Although several studies have demonstrated the synergistic antitumor effects of PDT and immune checkpoint blockage (ICB), the detailed underlying mechanisms remain poorly understood. In this study, we investigated the immunological effects of PDT with talaporfin (Tal-PDT), a clinically approved photosensitizer, using bilateral tumor-bearing mouse models. Treatment with Tal-PDT on the tumor on one side of the mouse resulted in tumor growth inhibition on the untreated opposite side. This phenomenon, accompanied by tumor antigen-specific immune reactions, is indicative of an abscopal effect. When combined with anti PD-L1 Ab, synergistic antitumor effects were observed on both the laser-treated and untreated sides. Mechanistically, Tal-PDT enhanced the induction of XCR-1+ dendritic cells in the proximal draining lymph node likely through the induction of ferroptosis in tumor cells. This, in turn, led to the systemic generation of precursor-exhausted CD8+ T cells. Moreover, talaporfin was selectively incorporated into tumor cells rather than into tumor-infiltrating T cells in vivo, leading to targeted tumor killing while preserving T cells. These beneficial effects of Tal-PDT on anti-tumor immunity collectively enhance ICB cancer immunotherapy. Our study demonstrates the potential of combining Tal-PDT with ICB therapy for clinical applications.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143023421","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}

引用次数: 0

Pathogenesis of IgA nephropathy as a tissue-specific autoimmune disease. 作为一种组织特异性自身免疫疾病的 IgA 肾病的发病机制。

IF 4.8 4区医学

International immunology Pub Date : 2024-12-26 DOI: 10.1093/intimm/dxae047

Yoshihito Nihei, Daisuke Kitamura

{"title":"Pathogenesis of IgA nephropathy as a tissue-specific autoimmune disease.","authors":"Yoshihito Nihei, Daisuke Kitamura","doi":"10.1093/intimm/dxae047","DOIUrl":"10.1093/intimm/dxae047","url":null,"abstract":"Glomerulonephritis (GN) is a group of heterogeneous immune-mediated kidney diseases that causes inflammation within the glomerulus. Autoantibodies (auto-Abs) are considered to be central effectors in the pathogenesis of several types of GN. Immunoglobulin A nephropathy (IgAN) is the most common GN worldwide and is characterized by the deposition of IgA in the glomerular mesangium of the kidneys, which is thought to be mediated by immune complexes containing non-specific IgA. However, we recently reported that IgA auto-Abs specific to mesangial cells (anti-mesangium IgA) were found in the sera of gddY mice, a spontaneous IgAN model, and patients with IgAN. We identified two autoantigens (β2-spectrin and CBX3) that are selectively expressed on the mesangial cell surface and targeted by anti-mesangial IgA. Our findings redefined IgAN as a tissue-specific autoimmune disease. Regarding the mechanisms of production of anti-mesangium IgA, studies using gddY mice have revealed that the production of anti-CBX3 IgA is induced by particular strains of commensal bacteria in the oral cavity, possibly through their molecular mimicry to CBX3. Here, we discuss a new concept of IgAN pathogenesis from the perspective of this disease as autoimmune GN caused by tissue-specific auto-Abs.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"75-81"},"PeriodicalIF":4.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765984","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}

引用次数: 0

PP2A negatively regulates NK cell T-bet expression and anti-tumor effector function. PP2A 负向调节 NK 细胞 T-bet 的表达和抗肿瘤效应功能。

IF 4.8 4区医学

International immunology Pub Date : 2024-12-26 DOI: 10.1093/intimm/dxae057

Yui Shinzawa, Daisuke Hara, Yuki Shinguryo, Satoru Yokoyama, Manabu Kawada, Yoshihiro Hayakawa

{"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":"10.1093/intimm/dxae057","url":null,"abstract":"The transcription factor T-bet is essential for the anti-tumor effector function of natural killer (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 protein phosphatase 2A (PP2A)-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expression of T-bet and its downstream effector molecules, granzyme B and IFN-γ, was 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.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"97-107"},"PeriodicalIF":4.8,"publicationDate":"2024-12-26","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}

引用次数: 0

A splice of life: the discovery, function, and clinical implications of FOXP3 isoforms in autoimmune disease. "生命的剪接：FOXP3 同工酶在自身免疫性疾病中的发现、功能和临床意义"。

IF 4.8 4区医学

International immunology Pub Date : 2024-12-26 DOI: 10.1093/intimm/dxae049

Kristin N Weinstein, Phillip P Domeier, Steven F Ziegler

{"title":"A splice of life: the discovery, function, and clinical implications of FOXP3 isoforms in autoimmune disease.","authors":"Kristin N Weinstein, Phillip P Domeier, Steven F Ziegler","doi":"10.1093/intimm/dxae049","DOIUrl":"10.1093/intimm/dxae049","url":null,"abstract":"Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in the development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.","PeriodicalId":13743,"journal":{"name":"International immunology","volume":" ","pages":"83-90"},"PeriodicalIF":4.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141971053","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}

引用次数: 0