CD8 Cell Division Maintaining Cytotoxic Memory Occurs Predominantly in the Bone Marrow

Parretta, Elisabetta; Cassese, Giuliana; Barba, Pasquale; Santoni, Angela; Guardiola, John; Rosa, Francesca Di

doi:10.4049/jimmunol.174.12.7654

Cited by 123 publications

(190 citation statements)

References 71 publications

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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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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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“…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%

“…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.…”

Section: Francesca DI Rosamentioning

confidence: 64%

“…Moreover, they have suggested that bone marrow memory CD8 + T cells are sessile, as up to 60% of them express CD69, a molecule that in CD4 + T cells is essential for retention in the bone marrow 8,9 . Finally, they suggest that the colocalization of bone marrow memory CD8 + T cells with IL-7-producing stromal cells supports the idea of IL-7-driven survival of memory CD8 + T cells in the absence of proliferation 9 .However, it could be argued that although the frequency of memory CD8 + T cells that are dividing in the bone marrow is low, the absolute numbers of proliferating memory CD8 + T cells is much higher in the bone marrow than in the spleen and lymph nodes 3,4 . 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 .…”

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confidence: 88%

“…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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CMV‐specific central memory T cells reside in bone marrow

Letsch

Knödler

et al. 2007

Eur J Immunol

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CMV-specific CD8 + T cell responses in peripheral blood (PB) are characterized by a preponderance of effector and effector memory T cells. CMV-specific central memory T cells (T CM ), which are considered crucial in maintaining long-term immunity, are rarely detectable in PB. In this study we have analyzed differentiation and function of CMV pp65-specific CD8 + T cells in paired samples of human PB and BM using intracellular cytokine and tetramer staining. Overall frequencies of CMV pp65-specific T cells were similar in PB compared to BM; however, CMV-specific CD45RA -CCR7 + T CM were almost exclusively detectable in BM, which was not related to a general accumulation of T CM in BM. In vitro, CMV-specific T cells could be more efficiently expanded from BM (median 128-fold, n=6) than from PB (median 72-fold, p=0.01). Taken together, these data show that the BM is a compartment harboring CMV-specific T CM and underline the concept of the BM as a secondary immune organ. CMV specific BM-derived T CM might be a valuable source for generating T cells for adoptive transfer. IntroductionBased on phenotypic and functional characteristics two main populations of memory T cells can be distinguished: central memory T cells (T CM ), expressing the chemokine receptor CCR7, and effector memory T cells (T EM ), lacking lymph node homing receptors and migrating to peripheral tissues [1]. Both subsets can differentiate into effector T cells (T Eff ). The generally accepted concept holds that T CM have a higher proliferative potential and a greater capacity than T EM for long-lasting persistence in vivo [2][3][4].There is growing evidence suggesting that CD8 + T CM play a key role in long-term protection against acute infections in vivo [5][6][7]. In the chronic phase of persistent infections, differences in T cell differentiation were found dependent on viral specificity [8]. In general, specific CD8 + T cell responses against CMV and other chronic viral infections found in peripheral blood (PB) were CCR7 -belonging to T EM and T EFF [8][9][10][11]. It is unclear yet, whether the failure to detect CMV-specific CCR7 + T CM is related to the specific situation of chronic infection, where continuous stimulation of T cells occurs, or is due to their retention in lymphoid tissues. Information concerning the anatomical distribution of T cell differentiation subsets of virusspecific T cells in humans is very limited. In the study by Ellefsen et al.[10], however, several fold lower * These two authors contributed equally to this work. frequencies of CMV pp65-specific tetramer + CD8 + T cells were found in lymph nodes compared to PB. Recently the BM was identified as an important site for accumulation and proliferation of memory T cells [12][13][14]. Furthermore, there is growing evidence of the BM as secondary lymphoid organ priming naive T cells (T N ) and also efficiently stimulating memory T cells [15,16].In this study we comparatively analyzed the differentiation subsets of CMV pp65-specific CD8 + T cells in human PB and BM samples o...

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CD8 Cell Division Maintaining Cytotoxic Memory Occurs Predominantly in the Bone Marrow

Cited by 123 publications

References 71 publications

Immunological memories of the bone marrow

Immunological memories of the bone marrow

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

CMV‐specific central memory T cells reside in bone marrow

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