Immune ageing is a result of repetitive microbial challenges along with cell intrinsic or systemic changes occurring during ageing. Mice under ‘specific-pathogen-free’ (SPF) conditions are frequently used to assess immune ageing in long-term experiments. However, physiological pathogenic challenges are reduced in SPF mice. The question arises to what extent murine experiments performed under SPF conditions are suited to analyze immune ageing in mice and serve as models for human immune ageing. Our previous comparisons of same aged mice with different microbial exposures, unambiguously identified distinct clusters of immune cells characteristic for numerous previous pathogen encounters in particular in pet shop mice. We here performed single cell mass cytometry assessing splenic as secondary and bone marrow as primary lymphoid organ-derived leukocytes isolated from young versus aged SPF mice in order to delineate alterations of the murine hematopoietic system induced during ageing. We then compared immune clusters from young and aged SPF mice to pet shop mice in order to delineate alterations of the murine hematopoietic system induced by physiological pathogenic challenges and those caused by cell intrinsic or systemic changes during ageing. Notably, distinct immune signatures were similarly altered in both pet shop and aged SPF mice in comparison to young SPF mice, including increased frequencies of memory T lymphocytes, effector-cytokine producing T cells, plasma cells and mature NK cells. However, elevated frequencies of CD4+ T cells, total NK cells, granulocytes, pDCs, cDCs and decreased frequencies of naïve B cells were specifically identified only in pet shop mice. In aged SPF mice specifically the frequencies of splenic IgM+ plasma cells, CD8+ T cells and CD4+ CD25+ Treg were increased as compared to pet shop mice and young mice. Our study dissects firstly how ageing impacts both innate and adaptive immune cells in primary and secondary lymphoid organs. Secondly, it partly distinguishes murine intrinsic immune ageing alterations from those induced by physiological pathogen challenges highlighting the importance of designing mouse models for their use in preclinical research including vaccines and immunotherapies.

中文翻译：

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小鼠造血系统的高维单细胞团流式细胞术分析揭示了衰老和生理病原体挑战诱导的特征

免疫衰老是重复性微生物挑战以及衰老过程中发生的细胞内在或全身变化的结果。“无特定病原体” (SPF) 条件下的小鼠经常用于评估长期实验中的免疫老化。然而，SPF 小鼠的生理致病性挑战减少了。问题是在 SPF 条件下进行的小鼠实验在多大程度上适合分析小鼠的免疫衰老并作为人类免疫衰老的模型。我们之前对具有不同微生物暴露的同龄小鼠进行了比较，明确确定了不同的免疫细胞群，这些免疫细胞群具有许多以前遇到的病原体的特征，特别是在宠物店小鼠中。我们在这里进行了单细胞质量流式细胞术，评估脾脏作为次级和骨髓作为初级淋巴器官来源的白细胞，这些白细胞从年轻和年老的 SPF 小鼠中分离出来，以描绘衰老过程中诱导的小鼠造血系统的改变。然后，我们将来自年轻和老年 SPF 小鼠的免疫簇与宠物店小鼠的免疫簇进行了比较，以描绘由生理致病性挑战引起的小鼠造血系统的变化以及衰老过程中细胞内在或全身变化引起的变化。值得注意的是，与年轻的 SPF 小鼠相比，宠物店和老年 SPF 小鼠的不同免疫特征发生了类似的改变，包括记忆 T 淋巴细胞、产生效应细胞因子的 T 细胞、浆细胞和成熟 NK 细胞的频率增加。然而，CD4+ T 细胞、总 NK 细胞、粒细胞、pDCs、cDCs 和初始 B 细胞频率降低仅在宠物店小鼠中被特异性识别。在老年 SPF 小鼠中，与宠物店小鼠和年轻小鼠相比，脾脏 IgM+ 浆细胞、CD8+ T 细胞和 CD4+ CD25+ Treg 的频率增加。我们的研究首先剖析了衰老如何影响初级和次级淋巴器官中的先天性和适应性免疫细胞。其次，它部分地将鼠内在免疫衰老改变与生理病原体挑战引起的改变区分开来，突出了设计用于临床前研究（包括疫苗和免疫疗法）的小鼠模型的重要性。在老年 SPF 小鼠中，与宠物店小鼠和年轻小鼠相比，脾脏 IgM+ 浆细胞、CD8+ T 细胞和 CD4+ CD25+ Treg 的频率增加。我们的研究首先剖析了衰老如何影响初级和次级淋巴器官中的先天性和适应性免疫细胞。其次，它部分地将鼠内在免疫衰老改变与生理病原体挑战引起的改变区分开来，突出了设计用于临床前研究（包括疫苗和免疫疗法）的小鼠模型的重要性。在老年 SPF 小鼠中，与宠物店小鼠和年轻小鼠相比，脾脏 IgM+ 浆细胞、CD8+ T 细胞和 CD4+ CD25+ Treg 的频率增加。我们的研究首先剖析了衰老如何影响初级和次级淋巴器官中的先天性和适应性免疫细胞。其次，它部分地将鼠内在免疫衰老改变与生理病原体挑战引起的改变区分开来，突出了设计用于临床前研究（包括疫苗和免疫疗法）的小鼠模型的重要性。