Maintenance of CD8<sup>+</sup> memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation

Siracusa, Francesco; Sercan, Özen; Maschmeyer, Patrick; McGrath, Mairi; Mashreghi, Mir‐Farzin; Hojyo, Shintaro; Chang, Hyun‐Dong; Tokoyoda, Koji; Radbruch, Andreas

doi:10.1002/eji.201747063

Cited by 33 publications

(52 citation statements)

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“…And finally, ablation of proliferating memory T cells in mice, using cyclophosphamide, shows that within 14 days, memory CD8 + T cells of the bone marrow are not deleted at all, contrary to their splenic counterparts, as discussed above. This is true for memory T cells of an intentional immune response as well as for the entire population of all CD8 + memory T cells of the bone marrow, those generated by natural infections over time in these mice 114. It should be noted that this is true also in the presence of Fingolimod (FTY720), blocking sphingosine‐1‐phosphate‐mediated trafficking of lymphocytes, and emptying the murine blood of lymphocytes.…”

Section: The Bone Marrow—hub For Circulating or Home Of Resident Memomentioning

confidence: 94%

“…We recently confirmed this finding, using cyclophosphamide to ablate proliferating CD8 + memory T cells in vivo. About 50% of all CD8 + memory T cells from spleen, as well as 50% of splenic memory CD8 + T cells generated in an intentional immune response, were ablated within 2 weeks of cyclophosphamide treatment 114. Interestingly, already 1 week of cyclophosphamide treatment was sufficient to ablate 50% of all CD8 + memory T cells from spleen, suggesting that 50% of the antigen‐experienced T cells of the spleen are rapidly proliferating, while the other 50% are not proliferating at all.…”

Section: The Lifestyle Of Circulating Memory T Lymphocytesmentioning

confidence: 99%

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Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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Section: The Bone Marrow—hub For Circulating or Home Of Resident Memomentioning

confidence: 94%

Section: The Lifestyle Of Circulating Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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“…In conclusion, the results of Siracusa et al. are important for stimulating discussion and research in the field to resolve these key issues.…”

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confidence: 88%

“…Nevertheless, the findings of Siracusa et al. challenge our view on how memory CD8 T cells are maintained and suggest that the underlying mechanism may differ per organ.…”

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confidence: 92%

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Maintenance of memory CD8 T cells: Divided over division

2017

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Once generated during an infection, memory CD8+ T cells can provide long-lasting protection against reinfection with an intracellular pathogen, but the longevity of this defense depends on the ability of these pathogen-specific memory cells to be maintained. Figure 1. Siracusa et al. [13] show that in the spleen, CD8 memory T cells are rapidly depleted upon CyP treatment, as they undergo homeostatic proliferation. In contrast, CD8 memory T cells in the BM are mostly quiescent, and thus protected from immediate depletion by CyP. These differences could be due to the supporting cell types that are present in spleen and bone marrow (e.g, more dendritic cells in the spleen), and/or differential expression of homeostatic cytokines.which are rapidly killed by CyP treatment (Fig. 1). Importantly, by treating mice with the drug FTY720, which inhibits egress of lymphocytes from lymphoid organs, the authors demonstrate that maintenance of memory CD8 T cells in the BM upon CyP treatment is not caused by a compensatory influx of peripheral CD8 T cells. A caveat of the study is that CyP also has some non-specific side-effects: CyP can deplete proliferating Tregs that in turn affect T cell homeostasis [15], and CyP has been shown to induce type 1 interferon and thereby increase proliferation of CD8 + memory T cells [16]. Nevertheless, the findings of Siracusa et al.[13] challenge our view on how memory CD8 T cells are maintained and suggest that the underlying mechanism may differ per organ. The conclusion that CD8 memory T cells in the BM are quiescent and do not proliferate, opposes previous studies from other groups regarding the maintenance of CD8 memory T cells in the BM. The group of Francesca di Rosa has published two papers showing that BM CD8 memory T cells contain a higher percentage of proliferating cells than their counterparts in either the spleen or lymph nodes, and this group proposed that the BM acts as a niche for antigen-independent proliferation of CD8 memory T cells [17,18]. Two other studies, of which one was in non-human primates, came to the same conclusion that homeostatic proliferation of memory CD8 T cells is most profound in the BM [12,19]. The discrepancies between the results of the Radbruch group and other groups regarding the proliferation of CD8 memory T cells in the BM remain unresolved, and could be due to many different factors. One key issue is the suspected induction of proliferation by BrdU treatment [10,18]. Most studies that have claimed higher proliferation of CD8 memory T cells in the BM as compared to the spleen, have done so based on BrdU incorporation by CD8 memory T cells [12,17,18]. In their 2015 study, Radbruch and colleagues showed that a 3 day treatment of 1 mg/mL BrdU in drinking water supplemented with sugar (which increases water consumption [20]) is sufficient to induce CD8 memory T-cell proliferation, with up to 75% of all CD8 memory T cells in the BM and spleen proliferating [10]. Of note, these percentages were much higher than those reported by the aforementioned stud...

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Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

Hradilkova

Maschmeyer

Westendorf

et al. 2019

Arthritis & Rheumatology

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Objective Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment. Methods Synovial and blood CD4+ T cells isolated ex vivo from patients with juvenile idiopathic arthritis (JIA) and murine CD4+ T cells were either stimulated once or stimulated repeatedly. Their dependency on particular metabolic pathways for survival was then analyzed using pharmacologic inhibitors. The role of the transcription factor Twist 1 was investigated by determining lactate production and oxygen consumption in Twist1‐sufficient and Twist1‐deficient murine T cells. The dependency of these murine cells on particular metabolic pathways was analyzed using pharmacologic inhibitors. Results Programmed death 1 (PD‐1)+ T helper cells in synovial fluid samples from patients with JIA survived via fatty acid oxidation (mean ± SEM survival of 3.4 ± 2.85% in the presence of etomoxir versus 60 ± 7.08% in the absence of etomoxir on day 4 of culture) (P < 0.0002; n = 6) and expressed the E‐box–binding transcription factor TWIST1 (2–14‐fold increased expression) (P = 0.0156 versus PD‐1− T helper cells; n = 6). Repeatedly restimulated murine T helper cells, which expressed Twist1 as well, needed Twist1 to survive via fatty acid oxidation. In addition, Twist1 protected the cells against reactive oxygen species. Conclusion Our findings indicate that TWIST1 is a master regulator of metabolic adaptation of T helper cells to chronic inflammation and a target for their selective therapeutic elimination.

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Maintenance of CD8⁺ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation

Cited by 33 publications

References 22 publications

Immunological memories of the bone marrow

Immunological memories of the bone marrow

Maintenance of memory CD8 T cells: Divided over division

Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

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Maintenance of CD8+ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation

Cited by 33 publications

References 22 publications

Immunological memories of the bone marrow

Immunological memories of the bone marrow

Maintenance of memory CD8 T cells: Divided over division

Regulation of Fatty Acid Oxidation by Twist 1 in the Metabolic Adaptation of T Helper Lymphocytes to Chronic Inflammation

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Maintenance of CD8⁺ memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation