RUI: The impact of malnutrition on T cell homeostasis

RUI：营养不良对 T 细胞稳态的影响

• 批准号: 1951881
• 负责人: Melanie Gubbels Bupp
• 金额: $ 61.01万
• 依托单位: Randolph-Macon College
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1951881&HistoricalAwards=false
• 关键词: RUI; impact; malnutrition; cell; homeostasis

During times of food shortages or malnutrition, organisms devote less energy to defending against infections. Indeed, malnutrition reduces the total number and functionality of specific immune cells. This may result in permanent deficiencies in immune defenses, even after adequate nutrition is restored. Data presented in this project suggest that organisms may have evolved mechanisms to minimize these immune defense deficiencies during malnutrition. This research explores the hypothesis that malnutrition triggers specific immune cells (T cells) to conserve energy to preserve a slightly larger number of immune cells, which ultimately minimizes the deleterious effects of malnutrition. Mice are used as a model organism to test this hypothesis. In the absence of infection, immune cells move in a coordinated fashion throughout the body. This behavior is critical for immune defense and is costly in terms of energy usage. This research will examine if malnourished immune cells disengage from these coordinated patterns of movement. Genetically-altered mice will also be studied to characterize the molecular pathways that may contribute to these energy-saving behaviors. Overall, this project will enable a better understanding of the mechanisms that contribute to the conservation of resources during malnutrition. This information may help researchers understand more about immunity in animals and humans. In addition, high-school Latinas and undergraduate research students will gain career mentorship and technical training related to experimental design, data acquisition and analysis, and scientific communication throughout this project. It is clear that the activation of the immune response is hindered during malnutrition. However, it is unclear how malnutrition affects the immune system in the absence of infection. The maintenance of a sufficiently large and diverse population of T cells (one type of antigen-specific adaptive immune cell) is critical for the initiation of a functional and appropriate immune response. This research explores a potential mechanism that may preserve a larger population of naïve T cells during short-term malnutrition. The hypothesis is that glucocorticoids act to quickly reduce the total number of peripheral T cells and induce an energy-saving, super-quiescent phenotype in T cells during malnutrition. Thus, this research will determine whether malnutrition reduces the number of naïve T cells via a glucocorticoid-dependent mechanism and if so, whether glucocorticoid upregulation of a particular cell surface receptor (CD127) is involved. Glucocorticoids will be inhibited in wild-type mice using known chemical glucocorticoid inhibitors. Complementary research will use mouse strains that have a conditional deletion of the glucocorticoid receptor in T cells, and mouse strains that have a selective mutation of glucocorticoid response elements upstream of the CD127 gene. These experimental systems will be used to determine if malnutrition eliminates rhythmic circadian T cell migration, reduces T cell migratory speed, redirects naïve T cells to temporarily reside in the bone marrow, or disrupts distinct lymph node entry efficiencies between CD4+ and CD8+ T cells utilizing the adoptive transfer of labeled T cells and flow cytometry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在食物短缺或营养不良的时期，生物体用于防御感染的能量较少。 事实上，营养不良会减少特定免疫细胞的总数和功能。这可能导致免疫防御的永久性缺陷，即使在恢复足够的营养之后。 该项目中提出的数据表明，生物体可能已经进化出了在营养不良期间最大限度地减少这些免疫防御缺陷的机制。 这项研究探讨了营养不良触发特定免疫细胞（T细胞）保存能量以保留稍多数量的免疫细胞的假设，最终最大限度地减少营养不良的有害影响。 小鼠被用作模型生物体来测试这一假设。在没有感染的情况下，免疫细胞以协调的方式在整个身体中移动。这种行为对于免疫防御至关重要，并且在能量使用方面是昂贵的。这项研究将检查营养不良的免疫细胞是否脱离这些协调的运动模式。 还将研究转基因小鼠，以表征可能有助于这些节能行为的分子途径。 总的来说，该项目将使人们更好地了解营养不良期间有助于保护资源的机制。 这些信息可能有助于研究人员更多地了解动物和人类的免疫力。此外，高中拉丁裔和本科研究生将获得职业指导和技术培训相关的实验设计，数据采集和分析，并在整个项目的科学交流。很明显，免疫反应的激活在营养不良期间受到阻碍。然而，目前还不清楚营养不良如何影响免疫系统在没有感染。 维持足够大和多样化的T细胞群体（一种类型的抗原特异性适应性免疫细胞）对于启动功能性和适当的免疫应答至关重要。 这项研究探索了一种潜在的机制，可以在短期营养不良期间保留更多的幼稚T细胞。 假设糖皮质激素作用于快速减少外周T细胞的总数，并在营养不良期间诱导T细胞中的节能、超静止表型。 因此，这项研究将确定营养不良是否通过糖皮质激素依赖性机制减少幼稚T细胞的数量，如果是这样，是否涉及糖皮质激素上调特定的细胞表面受体（CD127）。 使用已知的化学糖皮质激素抑制剂抑制野生型小鼠中的糖皮质激素。补充研究将使用T细胞中糖皮质激素受体有条件缺失的小鼠品系，以及CD 127基因上游糖皮质激素反应元件有选择性突变的小鼠品系。这些实验系统将用于确定营养不良是否会消除节律性昼夜T细胞迁移，降低T细胞迁移速度，重新定向幼稚T细胞暂时驻留在骨髓中，或破坏CD4+和CD8+之间不同的淋巴结进入效率利用标记T细胞的过继转移和流式细胞术的T细胞。该奖项反映了NSF的法定使命，并被认为值得支持通过使用基金会的知识价值和更广泛的影响审查标准进行评估。

项目成果

Malnutrition Disrupts T Cell Migration

营养不良会破坏 T 细胞的迁移

• DOI: 10.4049/jimmunol.208.supp.167.08
• 发表时间: 2022
• 期刊: The Journal of Immunology
• 作者: Dadzie, Kwesi A.;Foster, Takesha R;Mister, Abigail;Goulmamine, Syreen;Gibson, David;Adams, Olivia;Gubbels-Bupp, Melanie R
• 通讯作者: Gubbels-Bupp, Melanie R

Distinct lymph node entry efficiencies for CD8+ and CD4+ T cells are eliminated during malnourishment.

CD8 和 CD4 T 细胞不同的淋巴结进入效率在营养不良期间被消除。

• DOI: 10.4049/jimmunol.206.supp.11.17
• 发表时间: 2021
• 期刊: The Journal of Immunology
• 作者: Bowman, Lauren A;Goulmamine, Syreen;Gibson, David;Little, Amie;Bupp, Melanie Gubbels
• 通讯作者: Bupp, Melanie Gubbels

Glucocorticoids redirect naive T cells to the bone marrow in malnourished mice

糖皮质激素将幼稚 T 细胞重定向至营养不良小鼠的骨髓

• DOI: 10.4049/jimmunol.210.supp.239.07
• 发表时间: 2023
• 期刊: The Journal of Immunology
• 作者: Pearson, Caroline;Saravanan, Rithanya;Marczak, Marissa;Washington, Aja;Foster, Takesha R;Dadzie, Nana;Hanes, Jacob;Moore, Lindsay;Mister, Abigail;Goulmamine, Syreen
• 通讯作者: Goulmamine, Syreen

The Effect of Malnutrition on T-cell Circadian Rhythms

营养不良对 T 细胞昼夜节律的影响

• DOI: 10.4049/jimmunol.208.supp.167.07
• 发表时间: 2022
• 期刊: The Journal of Immunology
• 作者: Foster, Takesha R.;Dadzie, Kwesi A;Adams, Olivia;Gubbels-Bupp, Melanie R
• 通讯作者: Gubbels-Bupp, Melanie R

Maintenance of the naive T cell population during malnutrition is associated with residency in the bone marrow

营养不良期间幼稚 T 细胞群的维持与骨髓中的驻留有关

• DOI: 10.4049/jimmunol.210.supp.239.05
• 发表时间: 2023
• 期刊: The Journal of Immunology
• 作者: Foster, Takesha R;Dadzie, Kwesi A.;Moore, Lindsay;Saravanan, Rithanya;Adams, Olivia;Washington, Aja;Gubbels Bupp, Melanie R
• 通讯作者: Gubbels Bupp, Melanie R