上皮内淋巴细胞 (IEL) 区室的扩张导致 γδ IEL 中的生物能谱增加并减少 IFNγ 的产生。,The Journal of Immunology

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上皮内淋巴细胞 (IEL) 区室的扩张导致 γδ IEL 中的生物能谱增加并减少 IFNγ 的产生。
The Journal of Immunology ( IF 3.6 ) Pub Date : 2023-08-10 , DOI: 10.4049/jimmunol.210.supp.150.20
Sara Alonso ₁ , Luo Jia ₁ , Alyssa Laguerta ₁ , Karen Edelblum _{1,

2}

Affiliation

摘要肠道γδ上皮内淋巴细胞（γδ IEL）是抵御病原体入侵的第一道防线。我们最近发现了一种可传播的过度增殖性 γδ IEL (γδ HYP) 表型，可以防止肠道感染，并且这些小鼠没有明显的肠道病理迹象。鉴于 IEL 在代谢上受到限制以防止异常激活，我们假设 γδ HYPIEL 的生物能学可能调节其效应器功能。电子显微镜显示，与 WT 相比，γδ HYPIEL 的线粒体数量增加了 70%（p=0.005），线粒体面积增加了 24%（p=0.04）。对 γδ IEL 的海马线粒体应激测定显示，与 WT 相比，γδ HYPIEL 的备用呼吸能力增加了 50% (p=0.014)。线粒体代谢被证明会影响 γδ T 细胞细胞因子的产生，同样，我们发现，与 WT 相比，PMA 和离子霉素刺激使 γδ HYP 中 IFNγ +γδ IEL 的频率降低了 59%（p<0.0001）。我们还观察到，与 WT 相比，γδ HYPIEL 表现出更高的 CD39 表达（p < 0.0001），并且与 CD39 negand CD39 intcells 相比，CD39 hisubset 产生更少的 IFNγ（p <0.0001）。在 IEL 刺激期间添加 ATP 合酶抑制剂寡霉素增加了WT和γδ HYPIEL的IFNγ产量分别增加了66％和44％(p＜0.0001)。总之，我们的数据表明，向高 CD39 表达和线粒体代谢升高的转变导致 γδ HYPIEL 中 IFNγ 的产生减少。对调节 γδ IEL 稳态和效应器功能的机制的进一步了解可能最终允许对粘膜监测进行微调，以提供针对肠道损伤或感染的保护，同时限制异常的细胞毒性。由NJCCR (COCR23PRF024) 支持

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Expansion of the intraepithelial lymphocyte (IEL) compartment results in an increased bioenergetic profile and reduced IFNγ production in γδ IELs.

Abstract Intestinal γδ intraepithelial lymphocytes (γδ IEL) serve as the first line of defense against pathogen invasion. We recently identified a transmissible hyperproliferative γδ IEL (γδ HYP) phenotype that protects against enteric infection, and these mice have no signs of overt intestinal pathology. Given that IELs are metabolically constrained to prevent aberrant activation, we hypothesized that the bioenergetics of γδ HYPIELs may regulate their effector function. Electron microscopy revealed a 70% increase in mitochondrial number (p=0.005) and 24% increase in mitochondrial area (p=0.04) in γδ HYPIELs relative to WT. Seahorse mitochondrial stress assays on γδ IELs showed a 50% increase in spare respiratory capacity in γδ HYPIELs compared to WT (p=0.014). Mitochondrial metabolism was shown to influence γδ T cell cytokine production, and similarly, we found that stimulation with PMA and ionomycin reduced the frequency of IFNγ +γδ IELs by 59% in γδ HYPrelative to WT (p<0.0001). We also observed that γδ HYPIELs exhibit higher CD39 expression compared to WT (p<0.0001), and a CD39 hisubset produces less IFNγ compared to CD39 negand CD39 intcells (p<0.0001) The addition of the ATP-synthase inhibitor oligomycin during IEL stimulation increased IFNγ production by both WT and γδ HYPIELs by 66% and 44%, respectively (p<0.0001). Together, our data demonstrate that the shift towards high CD39 expression and elevated mitochondrial metabolism contribute to decreased IFNγ production in γδ HYPIELs. Further understanding of the mechanisms regulating γδ IEL homeostasis and effector function may ultimately allow fine tuning of mucosal surveillance to confer protection against intestinal injury or infection while limiting aberrant cytotoxicity. Supported by NJCCR (COCR23PRF024)

更新日期：2023-08-10

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