Abstract
BackgroundImmune 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Immune ageing is a result of repetitive microbial challenges along with cell intrinsic or systemic changes occurring during ageing
Our study dissects firstly how ageing impacts both innate and adaptive immune cells in primary and secondary lymphoid organs. 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
We analyzed each immune cluster of three major leukocyte groups: (a) CD45+ CD138− CD3− TCRβ− CD19− innate cells, (b) B cells and (c) T cells and identified unique populations according to cell surface markers expression for each group of mice as indicated in the heat maps for spleen and bone marrow (Fig. 1b and e)
Summary
Immune ageing is a result of repetitive microbial challenges along with cell intrinsic or systemic changes occurring during 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 applied multidimensional mass cytometry to delineate differences in phenotypic and functional immune signatures in primary and secondary lymphoid organs (bone marrow and spleen, respectively) of old and young SPF mice, as well as pet shop mice from our previous study as the most characteristic mouse group with distinguished immune signatures for numerous previous pathogen encounters. Specific individual changes were identified in SPF-aged mice as well as in pet shop mice This emphasizes that, while certain aspects of immune ageing and related diseases may be studied in standard experimental mouse models, common SPF housing settings may have to be adapted in order to translate results to be relevant for a physiological human setting
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