Booth Jayaum S, Goldberg Eric, Patil Seema A, Barnes Robin S, Greenwald Bruce D, Sztein Marcelo B
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
Immun Ageing. 2021 Apr 19;18(1):19. doi: 10.1186/s12979-021-00227-y.
The impact of aging on the immune system is unequivocal and results in an altered immune status termed immunosenescence. In humans, the mechanisms of immunosenescence have been examined almost exclusively in blood. However, most immune cells are present in tissue compartments and exhibit differential cell (e.g., memory T cells -T) subset distributions. Thus, it is crucial to understand immunosenescence in tissues, especially those that are exposed to pathogens (e.g., intestine). Using a human model of oral live attenuated typhoid vaccine, Ty21a, we investigated the effect of aging on terminal ileum (TI) tissue resident memory T (T) cells. T provide immediate adaptive effector immune responsiveness at the infection site. However, it is unknown whether aging impacts T S. Typhi-responsive cells at the site of infection (e.g., TI). Here, we determined the effect of aging on the induction of TI S. Typhi-responsive T subsets elicited by Ty21a immunization.
We observed that aging impacts the frequencies of TI-lamina propria mononuclear cells (LPMC) T and T in both Ty21a-vaccinated and control groups. In unvaccinated volunteers, the frequencies of LPMC CD103- CD4+ T displayed a positive correlation with age whilst the CD4/CD8 ratio in LPMC displayed a negative correlation with age. We observed that elderly volunteers have weaker S. Typhi-specific mucosal immune responses following Ty21a immunization compared to adults. For example, CD103+ CD4+ T showed reduced IL-17A production, while CD103- CD4+ T exhibited lower levels of IL-17A and IL-2 in the elderly than in adults following Ty21a immunization. Similar results were observed in LPMC CD8+ T and CD103- CD8+ T cell subsets. A comparison of multifunctional (MF) profiles of both CD4+ and CD8+ T subsets between elderly and adults also showed significant differences in the quality and quantity of elicited single (S) and MF responses.
Aging influences tissue resident T S. Typhi-specific responses in the terminal ileum following oral Ty21a-immunization. This study is the first to provide insights in the generation of local vaccine-specific responses in the elderly population and highlights the importance of evaluating tissue immune responses in the context of infection and aging.
This study was approved by the Institutional Review Board and registered on ClinicalTrials.gov (identifier NCT03970304 , Registered 29 May 2019 - Retrospectively registered).
衰老对免疫系统的影响是明确的，会导致一种被称为免疫衰老的免疫状态改变。在人类中，免疫衰老的机制几乎仅在血液中进行了研究。然而，大多数免疫细胞存在于组织隔室中，并表现出不同的细胞（例如，记忆T细胞-T）亚群分布。因此，了解组织中的免疫衰老至关重要，尤其是那些暴露于病原体的组织（例如肠道）。我们使用口服减毒活伤寒疫苗Ty21a的人体模型，研究了衰老对回肠末端（TI）组织驻留记忆T（T）细胞的影响。T细胞在感染部位提供即时的适应性效应免疫反应。然而，衰老是否会影响感染部位（例如TI）对伤寒沙门氏菌有反应的T细胞尚不清楚。在这里，我们确定了衰老对Ty21a免疫引发的TI对伤寒沙门氏菌有反应的T亚群诱导的影响。
我们观察到，衰老影响了接种Ty21a疫苗组和对照组中TI固有层单核细胞（LPMC）T细胞和T细胞的频率。在未接种疫苗的志愿者中，LPMC CD103-CD4+T细胞的频率与年龄呈正相关，而LPMC中的CD4/CD8比值与年龄呈负相关。我们观察到，与成年人相比，老年志愿者在接种Ty21a疫苗后对伤寒沙门氏菌的特异性黏膜免疫反应较弱。例如，接种Ty21a疫苗后，老年人体内CD103+CD4+T细胞产生的IL-17A减少，而CD103-CD4+T细胞产生的IL-17A和IL-2水平低于成年人。在LPMC CD8+T细胞和CD103-CD8+T细胞亚群中也观察到了类似的结果。对老年人和成年人CD4+和CD8+T细胞亚群的多功能（MF）谱进行比较，结果还显示，在引发的单一（S）和MF反应的质量和数量方面存在显著差异。
衰老会影响口服Ty21a疫苗后回肠末端组织中驻留的对伤寒沙门氏菌有特异性反应的T细胞。本研究首次深入探讨了老年人群中局部疫苗特异性反应的产生，并强调了在感染和衰老背景下评估组织免疫反应的重要性。
本研究经机构审查委员会批准，并在ClinicalTrials.gov上注册（标识符NCT03970304，2019年5月29日注册-追溯注册）。
