Mucosal Immunology最新文献_第3页

Extracellular vesicles of Bacteroides uniformis induce M1 macrophage polarization and aggravate gut inflammation during weaning 均匀乳杆菌的胞外囊泡会诱导 M1 巨噬细胞极化，并加剧断奶期间的肠道炎症。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.05.004

Weaning process is commonly associated with gastrointestinal inflammation and dysbiosis of the intestinal microbes. In particular, the impact of gut bacteria and extracellular vesicles on the etiology of intestinal inflammation during weaning is not well understood. We have uncovered a potential link between gut inflammation and the corresponding variation of macrophage bacterial sensing and pro-inflammatory polarization during the weaning process of piglets through single-cell transcriptomic analyses. We conducted a comprehensive analysis of bacterial distribution across the gastrointestinal tract and pinpointed Bacteroides uniformis enriching in piglets undergoing weaning. Next, we found out that exposure to B. uniformis-derived extracellular vesicles (BEVs) exacerbated gut inflammation in a murine colitis model while recruiting and polarizing intestinal macrophages toward a pro-inflammatory phenotype. BEVs modulated the function of macrophages cultured in vitro by suppressing the granulocyte-macrophage colony-stimulating factor/signal transducer and activator of transcription 5/arginase 1 pathway, thereby affecting polarization toward an M1-like state. The effects of BEVs were verified both in the macrophage clearance murine model and by using an adoptive transfer assay. Our findings highlight the involvement of BEVs in facilitating the polarization of pro-inflammatory macrophages and promoting gut inflammation during weaning.

断奶过程通常与胃肠道炎症和肠道微生物菌群失调有关。尤其是肠道细菌和细胞外囊泡（EV）对断奶期间肠道炎症病因的影响尚不十分清楚。我们通过单细胞转录组分析发现了仔猪断奶过程中肠道炎症与巨噬细胞细菌感应和促炎极化的相应变化之间的潜在联系。我们对整个胃肠道的细菌分布进行了全面分析，发现均匀乳杆菌（B. uniformis）在断奶仔猪中富集。接下来，我们发现，在小鼠结肠炎模型中，暴露于均匀杆菌衍生的EVs（BEVs）会加剧肠道炎症，同时招募肠道巨噬细胞并使其极化为促炎表型。BEVs 通过抑制 GM-CSF/STAT5/ARG1 通路调节体外培养巨噬细胞的功能，从而影响向 M1 样态的极化。BEVs的作用在巨噬细胞清除小鼠模型中和通过采用转移试验都得到了验证。我们的研究结果突出表明，BEVs 参与促进促炎巨噬细胞的极化，并在断奶期间促进肠道炎症。

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引用次数: 0

Lung influenza virus-specific memory CD4 T cell location and optimal cytokine production are dependent on interactions with lung antigen-presenting cells 肺部流感病毒特异性记忆 CD4 T 细胞的位置和最佳细胞因子的产生取决于与肺部抗原呈递细胞的相互作用。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.001

Influenza A virus (IAV) infection leads to the formation of mucosal memory CD4 T cells that can protect the host. An in-depth understanding of the signals that shape memory cell development is required for more effective vaccine design. We have examined the formation of memory CD4 T cells in the lung following IAV infection of mice, characterizing changes to the lung landscape and immune cell composition. IAV-specific CD4 T cells were found throughout the lung at both primary and memory time points. These cells were found near lung airways and in close contact with a range of immune cells including macrophages, dendritic cells, and B cells. Interactions between lung IAV-specific CD4 T cells and major histocompatibility complex (MHC)II+ cells during the primary immune response were important in shaping the subsequent memory pool. Treatment with an anti-MHCII blocking antibody increased the proportion of memory CD4 T cells found in lung airways but reduced interferon-γ expression by IAV-specific immunodominant memory CD4 T cells. The immunodominant CD4 T cells expressed higher levels of programmed death ligand 1 (PD1) than other IAV-specific CD4 T cells and PD1+ memory CD4 T cells were located further away from MHCII+ cells than their PD1-low counterparts. This distinction in location was lost in mice treated with anti-MHCII antibodies. These data suggest that sustained antigen presentation in the lung impacts the formation of memory CD4 T cells by regulating their cytokine production and location.

甲型流感病毒（IAV）感染会导致粘膜记忆 CD4 T 细胞的形成，从而保护宿主。要想设计出更有效的疫苗，就必须深入了解影响记忆细胞发育的信号。我们研究了小鼠感染 IAV 后肺部记忆性 CD4 T 细胞的形成，分析了肺部结构和免疫细胞组成的变化。在原发和记忆时间点，整个肺部都发现了 IAV 特异性 CD4 T 细胞。这些细胞出现在肺部气道附近，并与一系列免疫细胞（包括巨噬细胞、树突状细胞和 B 细胞）密切接触。肺部 IAV 特异性 CD4 T 细胞和 MHCII+ 细胞在原发性免疫反应期间的相互作用对形成随后的记忆库非常重要。用抗MHCII阻断抗体治疗可增加肺气管中发现的记忆性CD4 T细胞的比例，但会降低IAV特异性免疫显性记忆性CD4 T细胞的干扰素-γ表达。免疫优势 CD4 T 细胞比其他 IAV 特异性 CD4 T 细胞表达更高水平的 PD1，PD1+ 记忆 CD4 T 细胞比 PD1 低的记忆 CD4 T 细胞远离 MHCII+ 细胞。在使用抗 MHCII 抗体治疗的小鼠中，这种位置上的差异消失了。这些数据表明，肺部持续的抗原呈递通过调节细胞因子的产生和位置影响了记忆性 CD4 T 细胞的形成。

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引用次数: 0

Activation of the SST-SSTR5 signaling pathway enhances corneal wound healing in diabetic mice 激活 SST-SSTR5 信号通路可促进糖尿病小鼠角膜伤口愈合

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.002

Corneal wound healing in diabetic patients is usually delayed and accompanied by excessive inflammation. However, the underlying cellular and molecular mechanisms remain poorly understood. Here, we found that somatostatin (SST), an immunosuppressive peptide produced by corneal nerve fibers, was significantly reduced in streptozotocin-induced diabetic mice. In addition, we discovered that topical administration of exogenous SST significantly improved re-epithelialization and nerve regeneration following diabetic corneal epithelial abrasion. Further analysis showed that topical SST significantly reduced the expression of injury inflammation-related genes, inhibited neutrophil infiltration, and shifted macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 in diabetic corneas' healing. Moreover, the application of L-817,818, an agonist of the SST receptor type 5 subtype, significantly reduced the inflammatory response following epithelial injury and markedly improved the process of re-epithelialization and nerve regeneration in mice. Taken together, these data suggest that activation of the SST-SST receptor type 5 pathway significantly ameliorates diabetes-induced abnormalities in corneal wound repair in mice. Targeting this pathway may provide a novel strategy to restore impaired corneal wound closure and nerve regeneration in diabetic patients.

糖尿病患者的角膜伤口愈合通常会延迟，并伴有过度炎症。然而，对其潜在的细胞和分子机制仍然知之甚少。在这里，我们发现由角膜神经纤维产生的一种免疫抑制肽--体节肽（SST）在链脲佐菌素诱导的糖尿病小鼠体内显著减少。此外，我们还发现，局部注射外源性 SST 能明显改善糖尿病角膜上皮擦伤后的再上皮化和神经再生。进一步的分析表明，在糖尿病角膜愈合过程中，外用 SST 能显著降低损伤炎症相关基因的表达，抑制中性粒细胞浸润，并使巨噬细胞极化从促炎性 M1 转向抗炎性 M2。此外，应用 SST 受体 5 型亚型激动剂 L-817,818 能显著减轻上皮损伤后的炎症反应，并明显改善小鼠的再上皮化和神经再生过程。综上所述，这些数据表明，激活 SST-SSTR5 通路可明显改善糖尿病引起的小鼠角膜伤口修复异常。靶向这一通路可能为恢复糖尿病患者受损的角膜伤口闭合和神经再生提供一种新策略。

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引用次数: 0

Cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways by CD101 CD101 对代谢、免疫调节和抗微生物途径的细胞特异性调节。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.004

T lymphocytes and myeloid cells express the immunoglobulin-like glycoprotein cluster of differentiation (CD)101, notably in the gut. Here, we investigated the cell-specific functions of CD101 during dextran sulfate sodium (DSS)-induced colitis and Salmonella enterica Typhimurium infection. Similar to conventional CD101^−/− mice, animals with a regulatory T cell-specific Cd101 deletion developed more severe intestinal pathology than littermate controls in both models. While the accumulation of T helper 1 cytokines in a CD101-deficient environment entertained DSS-induced colitis, it impeded the replication of Salmonella as revealed by studying CD101^−/− x interferon-g^−/− mice. Moreover, CD101-expressing neutrophils were capable to restrain Salmonella infection in vitro and in vivo. Both cell-intrinsic and -extrinsic mechanisms of CD101 contributed to the control of bacterial growth and spreading. The CD101-dependent containment of Salmonella infection required the expression of Irg-1 and Nox2 and the production of itaconate and reactive oxygen species. The level of intestinal microbial antigens in the sera of inflammatory bowel disease patients correlated inversely with the expression of CD101 on myeloid cells, which is in line with the suppression of CD101 seen in mice following DSS application or Salmonella infection. Thus, depending on the experimental or clinical setting, CD101 helps to limit inflammatory insults or bacterial infections due to cell type-specific modulation of metabolic, immune-regulatory, and anti-microbial pathways.

T 淋巴细胞和髓系细胞表达 Ig 样糖蛋白 CD101，尤其是在肠道中。在此，我们研究了 CD101 在 DSS 诱导的结肠炎和鼠伤寒沙门氏菌感染过程中的细胞特异性功能。与传统的 CD101-/- 小鼠相似，在这两种模型中，Treg 特异性 Cd101 缺失的动物比同种对照组出现了更严重的肠道病变。CD101缺陷环境中Th1细胞因子的积累可促进DSS诱导的结肠炎，但通过研究CD101-/- x IFN- γ-/-小鼠发现，Th1细胞因子的积累阻碍了沙门氏菌的复制。此外，表达 CD101 的中性粒细胞能够抑制沙门氏菌在体外和体内的感染。CD101的细胞内在和外在机制都有助于控制细菌的生长和扩散。CD101 依赖性抑制沙门氏菌感染需要 Irg-1 和 Nox2 的表达以及伊它康酸和活性氧的产生。IBD 患者血清中的肠道微生物抗原水平与髓细胞上 CD101 的表达成反比，这与小鼠应用 DSS 或沙门氏菌感染后 CD101 受抑制的情况一致。因此，根据实验或临床环境，CD101 可通过细胞类型特异性调节代谢、免疫调节和抗微生物途径，帮助限制炎症损伤或细菌感染。

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引用次数: 0

Human intestinal stromal cells promote homeostasis in normal mucosa but inflammation in Crohn’s disease in a retinoic acid–deficient manner 人类肠道基质细胞以缺乏维甲酸的方式促进正常粘膜的稳态，但在克罗恩病中则促进炎症。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.009

Intestinal stromal cells (SCs), which synthesize the extracellular matrix that gives the mucosa its structure, are newly appreciated to play a role in mucosal inflammation. Here, we show that human intestinal vimentin⁺CD90⁺smooth muscle actin⁻ SCs synthesize retinoic acid (RA) at levels equivalent to intestinal epithelial cells, a function in the human intestine previously attributed exclusively to epithelial cells. Crohn’s disease SCs (Crohn’s SCs), however, synthesized markedly less RA than SCs from healthy intestine (normal SCs). We also show that microbe-stimulated Crohn’s SCs, which are more inflammatory than stimulated normal SCs, induced less RA-regulated differentiation of mucosal dendritic cells (DCs) (circulating pre-DCs and monocyte-derived DCs), leading to the generation of more potent inflammatory interferon-γ^hi/interleukin-17^hi T cells than normal SCs. Explaining these results, Crohn’s SCs expressed more DHRS3, a retinaldehyde reductase that inhibits retinol conversion to retinal and, thus, synthesized less RA than normal SCs. These findings uncover a microbe–SC–DC crosstalk in which luminal microbes induce Crohn’s disease SCs to initiate and perpetuate inflammation through impaired synthesis of RA.

肠道基质细胞（SCs）合成细胞外基质，赋予粘膜结构，新近被认为在粘膜炎症中发挥作用。在这里，我们展示了人类肠道波形蛋白+CD90+SMA- SCs合成维甲酸（RA）的水平与肠道上皮细胞相当，而这种功能在人类肠道中以前被认为是上皮细胞的专有功能。然而，克罗恩病 SCs（克罗恩 SCs）合成的视黄酸明显少于健康肠道 SCs（正常 SCs）。我们还发现，微生物刺激的克罗恩病 SCs 比刺激的正常 SCs 具有更强的炎症性，它们诱导的由 RA 调节的粘膜 DCS（循环前 DCs 和单核细胞衍生 DCs）分化较少，从而产生了比正常 SCs 更强的炎症性 IFN-γhi/IL-17hi T 细胞。为了解释这些结果，克罗恩病 SCs 表达了更多的 DHRS3（一种抑制视黄醇转化为视黄醛的视黄醛还原酶），因此合成的 RA 比正常 SCs 少。这些发现揭示了微生物-SC-DC 之间的串联作用，其中管腔微生物诱导克罗恩病 SCs 通过受损的 RA 合成启动和延续炎症。

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引用次数: 0

Impaired neutrophil migration underpins host susceptibility to infectious colitis 中性粒细胞迁移障碍是宿主易患传染性结肠炎的基础。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.008

Citrobacter rodentium models infection with enteropathogenic Escherichia coli and ulcerative colitis (UC). While C57BL/6 (C57) mice recover, C3H/HeN (C3H) mice succumb to infection, partially due to increased colonic neutrophil elastase activity, also seen in UC patients; however, the underlying cause was unknown. Here, we found that bone marrow, blood, and colonic C57 neutrophils expressed (CD)11b^Hi and reached the infected colonic lumen, where they underwent productive NETosis. In contrast, while the number of C3H neutrophils increased in the bone marrow, blood, and colon, they remained CD11b^Lo and got trapped in the submucosa, away from C. rodentium, where they underwent harmful NETosis. CD11b^Lo neutrophils in C3H mice infected with CR_i9, which triggers expression of neutrophil chemoattractants, reached the colonization site, resulting in host survival. UC patient neutrophils also displayed decreased levels of the activation/differentiation markers CD16/CXCR4. These results, suggesting that neutrophil malfunction contributes to exacerbated colitis, provide insight for future therapeutic prospects.

枸橼酸杆菌（Citrobacter rodentium）是感染肠致病性大肠杆菌和溃疡性结肠炎（UC）的模型。C57BL/6（C57）小鼠可恢复健康，而C3H/HeN（C3H）小鼠则会因感染而死亡，部分原因是结肠中性粒细胞弹性蛋白酶活性增加，这在溃疡性结肠炎患者中也可见到；然而，其根本原因尚不清楚。在这里，我们发现骨髓、血液和结肠中的 C57 中性粒细胞表达 CD11bHi，并到达受感染的结肠腔，在那里进行生产性 NETosis。与此相反，虽然骨髓、血液和结肠中的 C3H 中性粒细胞数量增加，但它们仍然是 CD11bLo 中性粒细胞，并被困在粘膜下层，远离鼠疫杆菌，并在那里发生有害的 NETosis。C3H小鼠感染CRi9后，CD11bLo中性粒细胞会触发中性粒细胞趋化因子的表达，从而到达定植部位，导致宿主存活。UC 患者中性粒细胞的活化/分化标志物 CD16/CXCR4 水平也有所下降。这些结果表明，中性粒细胞功能失调导致结肠炎恶化，为未来的治疗前景提供了启示。

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引用次数: 0

Git2 deficiency promotes MDSCs recruitment in intestine via NF-κB-CXCL1/CXCL12 pathway and ameliorates necrotizing enterocolitis Git2 缺乏可通过 NF-κB-CXCL1/CXCL12 途径促进肠道中 MDSCs 的招募，并改善坏死性小肠结肠炎。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.07.006

Huijuan Le , Yanyan Wang , Jiefei Zhou , Dan Li , Zizhen Gong , Fangxinxing Zhu , Jian Wang , Chunyan Tian , Wei Cai , Jin Wu

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease in preterm infants and the most common cause of neonatal death, whereas the molecular mechanism of intestinal injury remains unclear accompanied by deficiency of effective therapeutic approaches. GIT2 (G-protein-coupled receptor kinase interacting proteins 2) can affect innate and adaptive immunity and has been involved in multiple inflammatory disorders. In this study, we investigated whether GIT2 participates in the pathogenesis of NEC. Here we found that intestinal Git2 gene expression was significantly increased in NEC patients and NEC mice, which positively correlated with the tissue damage severity, and Git2 deficiency could potently protect against NEC development in mice. Mechanistically, Git2 gene knockout dramatically increased the recruitment of MDSCs in the intestine, and in vivo depletion of MDSCs almost completely abrogated the protective effect of Git2 deficiency on NEC. Moreover, Git2 deficiency induced MDSCs intestinal accumulation mainly relied on CXCL1/CXCL12 signaling, as evidenced by the significant increment of CXCL1 and CXCL12 levels in intestinal epithelium of Git2^-/- mice and dramatically decrease of MDSCs accumulation in intestine as well as increase of NEC severity upon treatment of CXCL1/CXCL12 pathway inhibitors. In addition, Git2 deficiency induced up-regulation of CXCL1 and CXCL12 is at least partially mediated through activating NF-κB signaling. Thus, our findings suggest that GIT2 is involved in the pathogenesis of NEC, and targeting GIT2 may be a potential preventive and therapeutic approach for NEC.

坏死性小肠结肠炎（NEC）是早产儿的一种严重胃肠道疾病，也是新生儿死亡的最常见原因，但肠道损伤的分子机制仍不清楚，也缺乏有效的治疗方法。GIT2（G-蛋白偶联受体激酶相互作用蛋白 2）可影响先天性免疫和适应性免疫，并参与多种炎症性疾病。本研究探讨了 GIT2 是否参与了 NEC 的发病机制。我们发现，肠道 Git2 基因在 NEC 患者和 NEC 小鼠中的表达明显增加，与组织损伤的严重程度呈正相关，Git2 基因缺失可有效防止小鼠 NEC 的发生。从机理上讲，Git2 基因敲除可显著增加肠道内 MDSCs 的募集，而体内 MDSCs 的耗竭几乎完全减弱了 Git2 缺乏对 NEC 的保护作用。此外，Git2缺陷诱导的MDSCs肠道聚集主要依赖于CXCL1/CXCL12信号转导，这表现在Git2-/-小鼠肠上皮细胞中CXCL1和CXCL12水平显著升高，CXCL1/CXCL12通路抑制剂治疗后MDSCs肠道聚集显著减少，NEC严重程度增加。此外，Git2 缺乏诱导的 CXCL1 和 CXCL12 上调至少部分是通过激活 NF-κB 信号介导的。因此，我们的研究结果表明，GIT2 参与了 NEC 的发病机制，靶向 GIT2 可能是一种潜在的 NEC 预防和治疗方法。

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引用次数: 0

Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis 代谢活跃的嗜中性粒细胞是结核分枝杆菌的容许生态位。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.05.007

Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.

结核分枝杆菌（Mtb）感染的中性粒细胞经常出现在活动性结核病（TB）患者的呼吸道中，肺部中性粒细胞的过度募集与结核病的细菌负荷增加和病理恶化有关。中性粒细胞对 Mtb 的容许性以及在结核病中致病的能力一直难以捉摸。在这里，我们确定了中性粒细胞的代谢和功能特征，这些特征有助于它们在 Mtb 感染中的致病性。通过单细胞代谢和转录分析，我们发现受 Mtb 感染的肺部中性粒细胞线粒体代谢升高，这主要归因于诱导了代谢活性增强的活化中性粒细胞。在Mtb感染的非人灵长类肺肉芽肿中也发现了活化的中性粒细胞亚群。从功能上讲，活化的中性粒细胞可包藏更多有活力的细菌，并显示出更强的脂质摄取和积累能力。令人惊讶的是，我们发现 IFNγ 在 Mtb 感染期间促进了肺中性粒细胞的活化。最后，对脂质摄取途径的干扰选择性地损害了Mtb在活化的中性粒细胞中的存活。这些研究结果表明，中性粒细胞的异质性和代谢多样性是它们对Mtb的容许性的关键，中性粒细胞中的代谢途径是结核病的潜在宿主导向疗法。

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引用次数: 0

Atopic dermatitis and food allergy: More than sensitization 特应性皮炎与食物过敏：不仅仅是过敏。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.005

The increased risk of food allergy in infants with atopic dermatitis (AD) has long been recognized; an epidemiologic phenomenon termed “the atopic march.” Current literature supports the hypothesis that food antigen exposure through the disrupted skin barrier in AD leads to food antigen-specific immunoglobulin E production and food sensitization. However, there is growing evidence that inflammation in the skin drives intestinal remodeling via circulating inflammatory signals, microbiome alterations, metabolites, and the nervous system. We explore how this skin-gut axis helps to explain the link between AD and food allergy beyond sensitization.

患有特应性皮炎的婴儿发生食物过敏的风险增加早已得到公认；这种流行病学现象被称为 "特应性进展"。目前的文献支持这样一种假设，即特应性皮炎患者通过破坏皮肤屏障接触食物抗原会导致食物抗原特异性 IgE 的产生和食物过敏。然而，越来越多的证据表明，皮肤炎症会通过循环炎症信号、微生物组改变、代谢物和神经系统驱动肠道重塑。我们将探讨皮肤-肠道轴如何帮助解释特应性皮炎与食物过敏之间的联系，而不仅仅是过敏。

引用次数: 0

Regulatory T cells restrict immunity and pathology in distal tissue sites following a localized infection 调节性 T 细胞限制了局部感染后远端组织部位的免疫和病理变化。

IF 7.9 2区医学 Q1 IMMUNOLOGY

Mucosal Immunology

Pub Date : 2024-10-01 DOI: 10.1016/j.mucimm.2024.06.007

Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of “mild” vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.

众所周知，调节性 T 细胞（Treg）在平衡状态下介导外周耐受性，而人们也越来越认识到它们在调节传染病免疫方面的作用。急性和慢性感染后，调节性 T 细胞可限制病原体特异性 T 细胞反应，从而限制免疫病理学。然而，目前还不清楚在局部感染期间，Tregs 是否能介导对远端组织部位病理和免疫的控制。我们以 "轻度 "阴道寨卡病毒（ZIKV）感染为背景，研究了Tregs在不同组织区免疫和疾病中的作用。我们发现，Tregs 对于在初始感染部位产生强大的病毒特异性 CD8 T 细胞反应至关重要。此外，Tregs 还能限制局部感染期间的炎性细胞因子和免疫病理；Treg 缺失的小鼠免疫反应失调会导致阴道和中枢神经系统（CNS）的 T 细胞浸润和免疫病理增加。重要的是，这些中枢神经系统浸润在感染 Treg 充足的小鼠时不会以同样的程度出现，因为在这种情况下不会出现中枢神经系统免疫病理。我们的数据表明，Tregs 是在粘膜感染部位产生强大的病毒特异性反应的必要条件，而 Treg 介导的旁观者炎症限制了感染部位和远端组织部位的免疫病理。

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引用次数: 0