Kinetics of In Vivo Proliferation and Death of Memory and Naive CD8 T Cells: Parameter Estimation Based on 5-Bromo-2′-Deoxyuridine Incorporation in Spleen, Lymph Nodes, and Bone Marrow

Parretta, Elisabetta; Cassese, Giuliana; Santoni, Angela; Guardiola, John; Vecchio, Antonia; Rosa, Francesca Di

doi:10.4049/jimmunol.180.11.7230

Cited by 73 publications

(117 citation statements)

References 32 publications

(51 reference statements)

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“…Moreover, global transcription data, CD69 expression profiles and colocalization in tissue sections do not address in vivo T cell migration. In fact, in situ-labelling studies and parabiosis experi ments have shown that memory T cells do recirculate to and from the bone marrow 5,6 .In conclusion, the available evidence supports the view that the bone marrow is a 'stopping point' where recirculating memory CD8 + T cells are stimulated to proliferate before continuing to move around the body 3,4,12,13 . Notably, lodging into the bone marrow is a competitive process among memory T cells 14 , which is an element to be considered especially in interpretation of adoptive transfer data 11,14 .…”

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confidence: 52%

“…As regards BrdU-related artefacts, they may occur at high BrdU doses 9 but seem uncommon at the standard BrdU dose that was used in bone marrow T cell studies 3,4,12 . Notably, recent adoptive transfer experiments in genetically modified mice have shown that IL-15 in the bone marrow promotes proliferation and inhibits interleukin-7 receptor subunit-α (IL-7Rα) expression in memory CD8 + T cells, independently of antigen co-transfer or treatment with innate receptor agonists 13 .…”

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confidence: 99%

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Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

Rosa

2016

Nat Rev Immunol

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Six years ago, Radbruch and colleagues discussed in Nature Reviews Immunology (Organization of immunological memory by bone marrow stroma. Nat. Rev. Immunol. 10, 193-200 (2010)) 1 how distinct stromal cell subsets in the bone marrow can support the lifelong persistence of plasma cells and memory T cells. These authors proposed that the bone marrow might serve as a depot for resting noncirculating memory T cells. Furthermore, they discussed how memory T cells might be maintained in the bone marrow by survival factors, such as interleukin-7 (IL-7), as opposed to by proliferative factors, such as IL-15. This view was in contrast with the largely accepted notion at the time that recirculating memory T cells are maintained by a homeostatic equilibrium between proliferation and death long after antigen clearance 2 . Furthermore, it did not accommodate previous data concerning the proliferation 3,4 and recirculation 5,6 of memory CD8 + T cells in the bone marrow.Recently, the idea that was originally proposed in Nature Reviews Immunology 1 was revived by the identification of quiescent, non-migratory tissue-resident memory T (T RM ) cells in the skin, gut and other organs 7 . Indeed, Radbruch et al. hypothesized that bone marrow memory T cells might share several features with T RM cells, and they suggested that their previous and newly generated findings supported this concept 8,9 . However, it might be misleading to chiefly consider bone marrow memory T cells as non-circulating, non-dividing cells.Experiments using Ki67 staining in mice and humans have shown that, at any given time-point, 95-98% of memory CD8 + T cells in the bone marrow are in the G0 phase of the cell cycle 8,9 . Of the remaining cells, some are in the G1 interval, and a few (that is, 0.2-1.7%) are actively proliferating in S/G2/M 3,8,9 . However, this still means that the proportion of memory CD8 + T cells proliferating in the bone marrow is reproducibly two-to fourfold higher than the proportions (that is, 0.05-0.80%) proliferating in the spleen, lymph nodes or blood 3,8,9 . This is true also when cell division is measured for one or more days. For example, in a 3 day-bromodeoxyuridine (BrdU)-labelling analysis, the average frequency of dividing antigen-specific memory CD8 + T cells was 4% in the bone marrow and 2% in the spleen 4 . Moreover, when carboxyfluorescein succinimidyl ester (CFSE)-labelled antigen-specific memory CD8 + T cells were transferred into non-immunized animals, they showed higher rates of proliferation in the bone marrow than in the spleen and lymph nodes 3,10 . In general, the data concerning memory CD8 + T cell cycling in the bone marrow are all in agreement. However, memory CD4 + T cell proliferation requires further investigation, as antigen-specific cells have not been examined in the bone marrow 11 .Despite the apparent consistency of the data concerning memory CD8 + T cells, their interpretations differ. Radbruch's group proposes that these data suggest similarity between bone marrow memory CD8 + T cells and peripheral...

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confidence: 52%

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confidence: 99%

Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

Rosa

2016

Nat Rev Immunol

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“…Another indication for homeostatic proliferation of splenic memory T cells had come from analyses of the uptake of bromodeoxyuridine (BrdU) into their DNA, taken as a surrogate marker for proliferation 110, 111, 113. In those experiments, about 50% of the splenic memory CD8 + T cells had incorporated BrdU within 14 days.…”

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

confidence: 99%

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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“…Indeed, it has been reported that BrdU is toxic for various cell types, and may trigger an injury response leading to activation and division [21,22], which would perturb the normal population dynamics. Other laboratories found little toxicity of BrdU [23,24], and BrdU data have hitherto been interpreted under the assumption that BrdU does not influence the rates of cell proliferation or death.…”

Section: Introductionmentioning

confidence: 99%

“…Others [28][29][30] argued that labelled cells have recently divided, and that recently divided cells should have a faster death rate than non-divided unlabelled cells, which also allows for a decline of the fraction of BrdU þ cells. Several authors in the field of immunology [23,28,31] and in the field of haematopoietic stem cells [21,24,32] have argued that the loss of BrdU þ cells can be explained by BrdU dilution during the de-labelling phase. Indeed, the classical paper by Tough & Sprent [11] provided evidence for a decrease in BrdU mean fluorescence intensity (MFI) of BrdU þ memory phenotype T cells during the de-labelling phase.…”

Section: Introductionmentioning

confidence: 99%

A mechanistic model for bromodeoxyuridine dilution naturally explains labelling data of self-renewing T cell populations

Ganusov

Boer²

2013

J. R. Soc. Interface.

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Bromodeoxyuridine (BrdU) is widely used in immunology to detect cell division, and several mathematical models have been proposed to estimate proliferation and death rates of lymphocytes from BrdU labelling and delabelling curves. One problem in interpreting BrdU data is explaining the de-labelling curves. Because shortly after label withdrawal, BrdU þ cells are expected to divide into BrdU þ daughter cells, one would expect a flat down-slope. As for many cell types, the fraction of BrdU þ cells decreases during de-labelling, previous mathematical models had to make debatable assumptions to be able to account for the data. We develop a mechanistic model tracking the number of divisions that each cell has undergone in the presence and absence of BrdU, and allow cells to accumulate and dilute their BrdU content. From the same mechanistic model, one can naturally derive expressions for the mean BrdU content (MBC) of all cells, or the MBC of the BrdU þ subset, which is related to the mean fluorescence intensity of BrdU that can be measured in experiments. The model is extended to include subpopulations with different rates of division and death (i.e. kinetic heterogeneity). We fit the extended model to previously published BrdU data from memory T lymphocytes in simian immunodeficiency virusinfected and uninfected macaques, and find that the model describes the data with at least the same quality as previous models. Because the same model predicts a modest decline in the MBC of BrdU þ cells, which is consistent with experimental observations, BrdU dilution seems a natural explanation for the observed down-slopes in self-renewing populations.

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Kinetics of In Vivo Proliferation and Death of Memory and Naive CD8 T Cells: Parameter Estimation Based on 5-Bromo-2′-Deoxyuridine Incorporation in Spleen, Lymph Nodes, and Bone Marrow

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Cited by 73 publications

References 32 publications

Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

Maintenance of memory T cells in the bone marrow: survival or homeostatic proliferation?

Immunological memories of the bone marrow

A mechanistic model for bromodeoxyuridine dilution naturally explains labelling data of self-renewing T cell populations

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