Mucosal Immunology最新文献_第9页

MAIT cells exacerbate colonic inflammation in a genetically diverse murine model of spontaneous colitis MAIT细胞在遗传多样化的自发性结肠炎小鼠模型中加剧结肠炎症。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.05.006

Liyen Loh , David J. Orlicky , Andrea Spengler , Joanne Domenico , Jared Klarquist , Cassandra Levens , Sofia Celli , Jennifer M. Kofonow , Charles E. Robertson , Olivier Lantz , Francois Legoux , Daniel N. Frank , Jennifer Matsuda , Paul J. Norman , Kristine A. Kuhn , Joseph Onyiah , Laurent Gapin

IL-17-producing lymphocytes are involved in both tissue repair and the propagation of inflammation, with their effects highly context-dependent. Mucosal-Associated-Invariant-T-cells (MAIT), a subset of innate-like T cells with features of both Th1 and Th17 lineages, are increasingly recognized for their roles in mucosal immunity. Here, we identified the Collaborative-Cross CC011/Unc strain, which spontaneously develops chronic colitis, as being enriched for MAIT cells. This expansion coincides with an age-related loss of intestinal barrier permeability and colonic inflammation. Microbiota from CC011 mice activated MAIT cells in an MR1-dependent manner and selectively promoted the accumulation of MAIT17 cells in peripheral tissues. Single-cell transcriptomic analyses revealed colon MAIT cells from colitic CC011 mice expressed a pathogenic Th17-like signature, characterized by IL-1 and IL-23 signaling, IL-17A and IFNγ co-expression, and upregulation of IL-23R, features that correlated with inflammatory Ly6C^hi monocyte abundance. Genetic deletion of Traj33, essential for MAIT development, significantly reduced colonic inflammation in this model. These findings demonstrate that MAIT cells integrate microbial and cytokine cues to adopt a pathogenic effector phenotype that exacerbates chronic intestinal inflammation.

产生il -17的淋巴细胞参与组织修复和炎症的传播，其作用高度依赖于环境。粘膜相关不变T细胞（MAIT）是先天样T细胞的一个亚群，具有Th1和Th17谱系的特征，因其在粘膜免疫中的作用而越来越得到认可。在这里，我们鉴定了自发发生慢性结肠炎的协作交叉CC011/Unc菌株，富集了MAIT细胞。这种扩张与年龄相关的肠屏障渗透性丧失和结肠炎症同时发生。来自CC011小鼠的微生物群以mr1依赖的方式激活MAIT细胞，并选择性地促进MAIT17细胞在外周组织中的积累。单细胞转录组学分析显示，结肠炎CC011小鼠的结肠MAIT细胞表达致病性th17样信号，其特征是IL-1和IL-23信号，IL-17A和IFNγ共表达，IL-23R上调，这些特征与炎性Ly6Chi单核细胞丰度相关。在该模型中，MAIT发育所必需的Traj33基因缺失显著减少了结肠炎症。这些发现表明，MAIT细胞整合微生物和细胞因子线索，采用致病效应表型，加剧慢性肠道炎症。

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引用次数: 0

Inducible, but not constitutive, pancreatic REG/Reg isoforms are regulated by intestinal microbiota and pancreatic diseases 诱导型而非构成型胰腺REG/ REG异构体受肠道微生物群和胰腺疾病的调节。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.05.003

Yixuan D. Zhou , Macy R. Komnick , Fabiola Sepulveda , Grace Liu , Elida Nieves-Ortiz , Kelsey Meador , Ornella Ndatabaye , Aliia Fatkhullina , Asha Bozicevich , Braden Juengel , Natalie J. Wu-Woods , Paulina M. Naydenkov , Johnathan Kent , Nathaniel Christiansen , Maria Lucia Madariaga , Piotr Witkowski , Rustem F. Ismagilov , Daria Esterházy

The REG/Reg gene locus encodes a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in humans and mice, the pancreas and gut differed in REG/Reg isoform levels and preferences, with the duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as “inducible” and others as “constitutive”. Indeed, in pancreatic ductal adenocarcinoma and pancreatitis models, only inducible Reg members were upregulated in the pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG/Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.

REG/ REG基因位点编码一个保守的强效抗菌蛋白家族，但也与胰腺炎相关。在这里，我们研究了REG/ REG家族成员是否在其基线表达水平和在胰腺和肠道中受到扰动时的调节能力方面存在差异。我们发现，在人类和小鼠中，胰腺和肠道在REG/ REG异构体水平和偏好上存在差异，其中十二指肠与胰腺最相似。胰腺腺泡细胞和肠上皮细胞是主要的REG产生细胞。肠道共生微生物在肠道和胰腺中调控相同的、选择的Reg成员的表达。这些Reg成员在转录起始位点附近具有最多的stat3结合位点，并且部分依赖于IL-22。因此，我们将它们归类为“诱导型”和其他“构成型”。事实上，在胰腺导管腺癌和胰腺炎模型中，胰腺中只有可诱导的Reg成员上调。胰腺紊乱时，肠道Reg表达保持不变，而胰腺炎在发病后不久就改变了十二指肠和粪便中的微生物组成。我们的研究揭示了REG/ REG异构体的不同使用和调节作为组织特异性先天免疫的机制，强调了胰腺和十二指肠的密切联系，并暗示肠道-胰腺通信轴导致协调的REG反应。

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引用次数: 0

RSV infection in neonatal mice and gastrointestinal microbiome alteration contribute to allergic predisposition 新生小鼠的RSV感染和胃肠道微生物组改变有助于过敏易感性。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.04.007

Alexander D. Ethridge , Kazuma Yagi , Llilian Arzola Martínez , Andrew J. Rasky , Susan B. Morris , Nicole R. Falkowski , Gary B. Huffnagle , Nicholas W. Lukacs

Severe respiratory syncytial virus (RSV) infection during infancy is associated with a 2 to 4-fold increased risk for the development of wheezing and asthma. Recent studies have implicated microbiome changes, either within the lung or gut, during early life can also affect the development of pulmonary disease. Our studies demonstrate long-term gastrointestinal and lung microbiome changes following early life (EL) RSV infection. To determine the respective roles of ELRSV infection and the gut microbiome, we performed germ-free neonatal infection and microbiome colonization using a microbiome from an uninfected animal followed by cockroach allergen (CRA)-induced asthma 4 weeks later. Germ-free animals with ELRSV infection displayed increased airway disease that was diminished by microbiome colonization, including airway hyperreactivity (AHR), mucus, and eosinophil infiltration. To address the role of virus induced gastrointestinal microbiome alterations, we utilized GF mice conventionalized with RSV-associated or naive microbiomes followed by CRA-induced disease. Transfer of neonatal microbiome taken during acute RSV infection did not alter the allergic response to CRA. However, the transfer of a naive adult microbiome conferred protection from enhanced AHR in response to CRA whereas an RSV associated microbiome did not. Taken together, our data indicate that microbiome alteration and early life RSV infection both contribute to allergic predisposition.

婴儿时期严重的呼吸道合胞病毒（RSV）感染与发生喘息和哮喘的风险增加2至4倍相关。最近的研究表明，在生命早期，肺部或肠道内的微生物组变化也会影响肺部疾病的发展。我们的研究证明了早期呼吸道合胞病毒感染后胃肠道和肺部微生物组的长期变化。为了确定ELRSV感染和肠道微生物组的各自作用，我们使用来自未感染动物的微生物组进行了无菌新生儿感染和微生物组定植，随后在4周后进行了蟑螂过敏原（CRA）诱导的哮喘。感染ELRSV的无菌动物表现出气道疾病增加，而微生物定植（包括气道高反应性（AHR）、粘液和嗜酸性粒细胞浸润）减少了气道疾病。为了研究病毒诱导的胃肠道微生物组改变的作用，我们使用了常规的带有rsv相关或原始微生物组的GF小鼠，随后使用了cra诱导的疾病。急性呼吸道合胞病毒感染期间新生儿微生物组的转移没有改变对CRA的过敏反应。然而，在CRA反应中，幼稚成人微生物组的转移对增强的AHR具有保护作用，而RSV相关微生物组则没有。综上所述，我们的数据表明微生物组改变和早期呼吸道合胞病毒感染都有助于过敏易感性。

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引用次数: 0

Living on the edge: Mucus-associated microbes in the colon 生活在边缘：结肠中与黏液相关的微生物。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.04.003

Mihovil Joja , Erica T. Grant , Mahesh S. Desai

The colonic mucus layer acts as a physicochemical barrier to pathogen invasion and as a habitat for mucus-associated microbes. This mucosal microbiome plays a crucial role in moderating mucus production, maintaining barrier integrity, and shaping the host immune response. However, unchecked mucin foraging may render the host vulnerable to disease. To better understand these dynamics in the mucus layer, it is essential to advance fundamental knowledge on how commensals bind to and utilize mucin as well as their interactions with both the host and their microbial neighbors. We present an overview of approaches for surveying mucus-associated bacteria and assessing their mucin-utilizing capacity, alongside a discussion of the limitations of existing methods. Additionally, we highlight how diet and host secretory immunoglobulin A interact with the mucosal bacterial community in the colon. Insights into this subset of the microbial community can guide therapeutic strategies to optimally support and modulate mucosal barrier integrity.

结肠黏液层作为病原体入侵的物理化学屏障和黏液相关微生物的栖息地。这种粘膜微生物群在调节粘液产生、维持屏障完整性和塑造宿主免疫反应中起着至关重要的作用。然而，未经检查的粘蛋白觅食可能使宿主易受疾病侵害。为了更好地理解黏液层中的这些动态，有必要进一步了解共生体如何结合和利用黏液蛋白，以及它们与宿主及其微生物邻居的相互作用。我们提出了研究黏液相关细菌和评估其黏液利用能力的方法概述，并讨论了现有方法的局限性。此外，我们强调饮食和宿主分泌免疫球蛋白A如何与结肠粘膜细菌群落相互作用。深入了解微生物群落的这一子集可以指导治疗策略，以最佳地支持和调节粘膜屏障的完整性。

引用次数: 0

Corrigendum to “Distinct cell death pathways induced by granzymes collectively protect against intestinal Salmonella infection” [Mucosal. Immun. 17 (2024) 1242–1255] “颗粒酶诱导的不同细胞死亡途径共同保护肠道沙门氏菌感染”[粘膜]的更正。免疫学。17 (2024)1242-1255]

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.06.003

Amanpreet Singh Chawla , Maud Vandereyken , Maykel Arias , Llipsy Santiago , Dina Dikovskaya , Chi Nguyen , Neema Skariah , Nicolas Wenner , Natasha B. Golovchenko , Sarah J. Thomson , Edna Ondari , Marcela Garzón-Tituaña , Christopher J. Anderson , Megan Bergkessel , Jay C.D. Hinton , Karen L. Edelblum , Julian Pardo , Mahima Swamy

引用次数: 0

Gut microbiota regulates intestinal goblet cell response and mucin production by influencing the TLR2-SPDEF axis in an enteric parasitic infection 肠道微生物群通过影响肠道寄生虫感染中的TLR2-SPDEF轴调节肠杯状细胞反应和粘蛋白产生。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.03.007

Yeganeh Yousefi , Zarin Haider , Jensine A. Grondin , Huaqing Wang , Sabah Haq , Suhrid Banskota , Tyler Seto , Michael Surette , Waliul I. Khan

Alterations in goblet cell biology constitute one of the most effective host responses against enteric parasites. In the gastrointestinal (GI) tract, millions of bacteria influence these goblet cell responses by binding to pattern recognition receptors such as toll-like receptors (TLRs). Studies suggest that the gut microbiota also interacts bidirectionally with enteric parasites, including Trichuris muris. Here, we study the roles of T. muris-altered microbiota and the TLR2-SPDEF axis in parasitic host defense. In acute T. muris infection, we observed altered gut microbiota composition, which, when transferred to germ-free mice, resulted in increased goblet cell numbers, Th2 cytokines and Muc2 expression, as well as increased Tlr2. Further, antibiotic (ABX)-treated TLR2^-/- mice, despite having received the same T. muris-altered microbiota, displayed diminished Th2 response, Muc2 expression, and, intriguingly, diminished SPDEF expression compared to wildtype counterparts. When infected with T. muris, SPDEF^-/- mice exhibited a reduced Th2 response and altered microbial composition compared to SPDEF^+/+, particularly on day 14 post-infection, and this microbiota was sufficient to alter host goblet cell response when transferred to ABX-treated mice. Taken together, our findings suggest the TLR2-SPDEF axis, via T. muris-induced microbial changes, is an important regulator of goblet cell function and host’s parasitic defense.

杯状细胞生物学的改变是宿主对肠道寄生虫最有效的反应之一。在胃肠道中，数以百万计的细菌通过结合模式识别受体（如toll样受体（TLRs））来影响杯状细胞的反应。研究表明，肠道微生物群也与肠道寄生虫双向相互作用，包括毛滴虫。在这里，我们研究了T. muris改变的微生物群和TLR2-SPDEF轴在寄生宿主防御中的作用。在急性T. muris感染中，我们观察到肠道微生物群组成的改变，当将其转移到无菌小鼠时，导致杯状细胞数量增加，Th2细胞因子和Muc2表达增加，以及Tlr2增加。此外，抗生素（ABX）处理的TLR2-/-小鼠，尽管接受了相同的T. muris改变的微生物群，但与野生型相比，表现出Th2反应减弱，Muc2表达减少，有趣的是，SPDEF表达减少。当感染T. muris时，与SPDEF+/+相比，SPDEF-/-小鼠表现出Th2应答降低和微生物组成改变，特别是在感染后第14天，当转移到abx处理小鼠时，这些微生物群足以改变宿主杯状细胞应答。综上所述，我们的研究结果表明，TLR2-SPDEF轴通过T. muris诱导的微生物变化，是杯状细胞功能和宿主寄生防御的重要调节因子。

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引用次数: 0

Hypertonic intranasal vaccines gain nasal epithelia access to exert strong immunogenicity 高渗鼻内疫苗可进入鼻腔上皮细胞，发挥强大的免疫原性。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.03.006

Soichiro Hashimoto , Toshiro Hirai , Koki Ueda , Mako Kakihara , Nagisa Tokunoh , Chikako Ono , Yoshiharu Matsuura , Kazuo Takayama , Yasuo Yoshioka

Intranasal vaccines potentially offer superior protection against viral infections compared with injectable vaccines. The immunogenicity of intranasal vaccines including adenovirus vector (AdV), has room for improvement, while few options are available for safe execution. In this study, we demonstrate that modifying a basic parameter of vaccine formulation, i.e., osmolarity, can significantly enhance the immunogenicity of intranasal vaccines. Addition of glycerol to AdV intranasal vaccine solutions, unlike other viscous additives, enhanced systemic and mucosal antibodies as well as resident memory T cells in the nasal tissues, which could protect nasal tissue and the lungs against influenza virus. While viscous glycerol could not prolong intranasal retention of solutes, it promoted AdV infection of nasal epithelial cells by facilitating AdV access to the nasal epithelial cell. The enhanced immunogenicity was induced by the hypertonicity of vaccine preparations and sodium chloride, glucose, and mannitol demonstrated the capacity to enhance immunogenicity. Moreover, hypertonic glycerol enhanced the immunogenicity of adjuvanted subunit intranasal vaccines, but not subunit vaccines without adjuvant or injectable vaccines. Overall, the delivery of intranasal vaccines to nasal epithelial cells could be improved through a simple approach, potentially resulting in stronger immunogenicity for certain vaccines.

与注射疫苗相比，鼻内疫苗有可能提供更好的病毒感染保护。包括腺病毒载体（AdV）在内的鼻内疫苗的免疫原性还有待提高，而安全接种的方案却不多。在这项研究中，我们证明了改变疫苗配方的一个基本参数，即渗透压，可以显著提高鼻内疫苗的免疫原性。与其他粘性添加剂不同，在 AdV 鼻内疫苗溶液中添加甘油可增强全身和粘膜抗体以及鼻腔组织中的常驻记忆 T 细胞，从而保护鼻腔组织和肺部免受流感病毒的侵袭。虽然粘性甘油不能延长溶质的鼻内滞留时间，但它能促进 AdV 进入鼻上皮细胞，从而促进 AdV 感染鼻上皮细胞。疫苗制剂的高渗性诱导了免疫原性的增强，氯化钠、葡萄糖和甘露醇都表现出了增强免疫原性的能力。此外，高渗甘油能增强佐剂亚单位鼻内疫苗的免疫原性，但不能增强无佐剂亚单位疫苗或注射疫苗的免疫原性。总之，鼻内疫苗向鼻上皮细胞的输送可以通过一种简单的方法得到改善，从而有可能增强某些疫苗的免疫原性。

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引用次数: 0

Anti-ST2 antibody reduces airway hyperresponsiveness mediated by monocyte-derived macrophages during influenza A infection 抗st2抗体降低甲型流感感染期间由单核细胞来源的巨噬细胞介导的气道高反应性。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.04.008

Rohin Chakraborty, Julia Chronopoulos, Rui Sun, Arina Morozan, Sydney Joy, Maziar Divangahi, Anne-Marie Lauzon, James G. Martin

Influenza A virus (IAV) infections trigger asthma attacks and cause airway hyperresponsiveness (AHR) in murine models. However, the mechanism by which AHR is induced remains to be fully elucidated. Here, we show that targeting the interleukin (IL)–33 suppression of tumorigenicity 2 (ST2) receptor complex with an anti-ST2 antibody during acute IAV infection of C57BL/6 mice reduced AHR, without affecting expansion of ILC2s and independently of IL-13. Among the lung inflammatory cells, the anti-ST2 antibody selectively reduced the monocyte-derived macrophages (MMs). Furthermore, AHR was reduced in C–C chemokine receptor 2 (CCR2)-knockout mice that have deficient MM recruitment. Depletion of MMs achieved by anti-Ly6C antibody administration also reduced AHR. The treatment of airway smooth muscle (ASM) with conditioned medium from IL-33-treated human THP-1-derived macrophages enhanced potassium chloride-induced ASM contraction. These findings suggest that MMs contribute to acute AHR following IAV infection in an IL-33-dependent manner, but independent of the ILC2/IL-13 axis. Additionally, IL-33 stimulates the release of macrophage-derived mediators that enhance airway smooth muscle contraction, offering a potential mechanistic basis for IAV-induced AHR.

在小鼠模型中，甲型流感病毒（IAV）感染引发哮喘发作并引起气道高反应性（AHR）。然而，引起AHR的机制仍有待于充分阐明。在这里，我们发现在C57BL/6小鼠急性IAV感染期间，靶向白介素(IL)-33抑制致瘤性2 （ST2）受体复合物，用抗ST2抗体降低AHR，不影响ILC2s的扩增，独立于IL-13。在肺炎性细胞中，抗st2抗体选择性地减少单核细胞源性巨噬细胞（MMs）。此外，在MM募集不足的C-C趋化因子受体2 （CCR2）敲除小鼠中，AHR降低。通过给药抗ly6c抗体实现mm的消耗也降低了AHR。用il -33处理的人thp -1来源的巨噬细胞的条件培养基治疗气道平滑肌（ASM）可增强氯化钾诱导的ASM收缩。这些发现表明mm以il -33依赖的方式参与IAV感染后的急性AHR，但不依赖于ILC2/IL-13轴。此外，IL-33刺激巨噬细胞来源的介质释放，增强气道平滑肌收缩，为iav诱导的AHR提供了潜在的机制基础。

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引用次数: 0

A multi-omics microbiome signature is associated with the benefits of gastric bypass surgery and is differentiated from diet induced weight loss through 2 years of follow-up 多组学微生物组特征与胃旁路手术的益处相关，并通过2 年的随访与饮食引起的体重减轻区分开来。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.04.002

Vancheswaran Gopalakrishnan , Chanchal Kumar , Ida Robertsen , Christopher Morehouse , Ben Sparklin , Shameer Khader , Ian Henry , Line Kristin Johnson , Jens K. Hertel , Hege Christensen , Rune Sandbu , Peter J. Greasley , Bret R. Sellman , Anders Åsberg , Shalini Andersson , Rasmus Jansson Löfmark , Jøran Hjelmesæth , Cecilia Karlsson , Taylor S. Cohen

Roux-en-Y gastric bypass (GBP) surgery is an effective treatment for reducing body weight and correcting metabolic dysfunction in individuals with severe obesity. Herein, we characterize the differences between very low energy diet (VLED) and GBP induced weight loss by multi-omic analyses of microbiome and host features in a non-randomized, controlled, single-center study. Eighty-eight participants with severe obesity were recruited into two arms – GBP versus VLED with matching weight loss for 6 weeks and 2-years of follow-up. A dramatic shift in the distribution of gut microbial taxa and their functional capacity was seen in the GBP group at Week 2 after surgery and was sustained through 2 years. Multi-omic analyses were performed after 6 weeks of matching weight loss between the GBP and VLED groups, which pointed to microbiome derived metabolites such as indoxyl sulphate as characterizing the GBP group. We also identified an inverse association between Streptococcus parasanguinis (an oral commensal) and plasma levels of tryptophan and tyrosine. These data have important implications, as they reveal a significant robust restructuring of the microbiome away from a baseline dysbiotic state in the GBP group. Furthermore, multi-omics modelling points to potentially novel mechanistic insights at the intersection of the microbiome and host.

Roux-en-Y胃旁路手术（GBP）是严重肥胖患者减轻体重和纠正代谢功能障碍的有效治疗方法。在此，我们在一项非随机、对照、单中心研究中，通过对微生物组和宿主特征的多组学分析，表征了极低能量饮食（VLED）和GBP诱导的体重减轻之间的差异。88名严重肥胖的参与者被招募到两组- GBP和VLED，并在6 周和2年的随访中匹配体重减轻。术后第2周，GBP组肠道微生物群分布及其功能能力发生了巨大变化，并持续了2 年。在GBP组和VLED组之间匹配体重减轻6 周后进行多组学分析，这表明微生物组衍生代谢物如硫酸吲哚酚是GBP组的特征。我们还发现副鳗链球菌（一种口服共生体）与血浆色氨酸和酪氨酸水平呈负相关。这些数据具有重要意义，因为它们揭示了在GBP组中，微生物组从基线生态不良状态进行了重大的稳健重组。此外，多组学建模指出了微生物组和宿主交叉的潜在的新机制见解。

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引用次数: 0

Diet-induced dyslipidemia enhances IFN-γ production in mycolic acid-specific T cells and affects mycobacterial control 饮食诱导的血脂异常增强了霉菌酸特异性T细胞中IFN-γ的产生并影响分枝杆菌的控制。

IF 7.6 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2025-08-01 DOI: 10.1016/j.mucimm.2025.04.009

Yen-Lin Lin, Chyung-Ru Wang

Dyslipidemia, characterized by altered lipid profiles, influences host immune responses against infections, including Mycobacterium tuberculosis (Mtb). While the effects of dyslipidemia on conventional T cell responses are well documented, its impact on group 1-CD1 restricted T cells, a distinct subset of lipid antigen-specific unconventional T cells, during Mtb infection remains unclear. In this study, we developed a double-transgenic mouse model expressing human group 1 CD1 (hCD1Tg) and mycolic acid (MA)-specific CD1b-restricted T cell receptor (DN1Tg) in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia affects the functionality of MA-specific T cells and their role in anti-Mtb immunity. We found that diet-induced dyslipidemia led to increased IFN-γ production by MA-specific T cells, which promoted mycobacterial clearance in vitro. Mechanistically, this enhanced IFN-γ production was associated with increased TCR signaling and enhanced glycolysis in DN1 T cells, rather than changes in antigen presentation by dendritic cells. However, dyslipidemia also increased apoptosis in DN1 T cells, which may have impaired their ability to control mycobacterial infection in vivo, resulting in reduced bacterial clearance. These findings highlight a complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in Mtb infection, providing insights for potential therapeutic strategies to mitigate dyslipidemia-induced changes in T-cell functions.

以脂质谱改变为特征的血脂异常影响宿主对感染的免疫反应，包括结核分枝杆菌（Mtb）。虽然血脂异常对常规T细胞反应的影响已被充分证明，但在结核分枝杆菌感染期间，它对1-CD1组限制性T细胞（脂质抗原特异性非常规T细胞的一个独特亚群）的影响仍不清楚。在这项研究中，我们建立了一种双转基因小鼠模型，在ragg缺乏和低密度脂蛋白受体缺乏的背景下表达人1组CD1 （hCD1Tg）和霉菌酸（MA）特异性cd1b限制性T细胞受体（DN1Tg），以研究饮食诱导的血脂异常如何影响MA特异性T细胞的功能及其在抗结核免疫中的作用。我们发现饮食诱导的血脂异常导致ma特异性T细胞产生IFN-γ增加，从而促进体外分枝杆菌清除。从机制上讲，这种增强的IFN-γ产生与DN1 T细胞中TCR信号的增加和糖酵解的增强有关，而不是树突状细胞抗原呈递的变化。然而，血脂异常也增加了DN1 T细胞的凋亡，这可能损害了它们在体内控制分枝杆菌感染的能力，导致细菌清除率降低。这些发现强调了结核分枝杆菌感染中饮食诱导的血脂异常和脂质抗原特异性t细胞反应之间的复杂相互作用，为减轻血脂异常诱导的t细胞功能变化的潜在治疗策略提供了见解。

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引用次数: 0