Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory

Okhrimenko, Anna; Grün, Joachim R.; Westendorf, Kerstin; Fang, Zhuo; Reinke, Simon; Roth, Philipp von; Wassilew, Georgi I.; Kühl, Anja A.; Kudernatsch, Robert; Demski, Sonya; Scheibenbogen, Carmen; Tokoyoda, Koji; McGrath, Mairi; Raftery, Martin; Schönrich, Günther; Serra, Alessandro; Chang, Hyun‐Dong; Radbruch, Andreas; Dong, Jun

doi:10.1073/pnas.1318731111

Cited by 158 publications

(259 citation statements)

References 44 publications

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“…According to staining of Ki‐67, more than 90% of murine bone marrow memory CD8 + T cells are in G0 of the cell cycle, more than 180 days after the onset of an intentional immune response, and less than 0.5% are in the S/G2/M phases of cell cycle 117. The same is true for human memory CD8 + and CD4 + T cells of bone marrow 33. 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.…”

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

confidence: 94%

“…For the establishment of bone marrow‐resident memory CD4 lymphocytes, we have shown that CD69 is essential 137. “Tissue‐resident” memory T cells have downregulated S1PR1, like CD69 + bone marrow memory T cells 33. “Tissue‐resident” memory T cells, despite expressing CD69, rest in terms of proliferation and expression of effector molecules 160, 163.…”

Section: “Tissue‐resident” Vs Bone Marrow‐resident Memory T Lymphocytesmentioning

confidence: 97%

“…Within CD38 high plasma cells of the bone marrow, further diversity has been described regarding expression of other surface molecules 28. Among those CD19 has raised some interest recently as a candidate marker for memory plasma cells maintaining long‐term memories,31, 32 similar to memory CD4 + T lymphocytes of the bone marrow, as will be discussed later 33. Apparently loss of CD19 expression can occur already at the transition from plasmablast to plasma cell34.…”

Section: Memory Plasma Cellsmentioning

confidence: 99%

“…Their transcriptomes are those of resting cells 33, 59, 81, 117. CD8 + memory T cells of the bone marrow express only about 0.6 pg of RNA per cell, as compared to activated CD8 + T cells, which express more than 10 pg of RNA per cell 117.…”

Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 99%

“…In absolute numbers, the human skin harbors almost twice as many CD45RO + T cells as the peripheral blood 160. Human bone marrow contains 3‐4 times as many CD45RO + T cells as peripheral blood 33. In peripheral tissues and in the bone marrow, the numbers of experienced T cells recognizing a particular antigen remain high over time, while numbers of their circulating counterparts drop.…”

Section: “Tissue‐resident” Vs Bone Marrow‐resident 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: “Tissue‐resident” Vs Bone Marrow‐resident Memory T Lymphocytesmentioning

confidence: 97%

Section: Memory Plasma Cellsmentioning

confidence: 99%

Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 99%

Section: “Tissue‐resident” Vs Bone Marrow‐resident 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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The immune system in multiple myeloma and precursor states: Lessons and implications for immunotherapy and interception

Dhodapkar

2022

American J Hematol

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Multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) are distinct disorders that likely originate in the setting of chronic immune activation. Evolution of these lesions is impacted by cross‐talk with both innate and adaptive immune systems of the host. Harnessing the immune system may, therefore, be an attractive strategy to prevent clinical malignancy. While clinical MM is characterized by both regional and systemic immune suppression and paresis, immune‐based approaches, particularly redirecting T cells have shown remarkable efficacy in MM patients. Optimal application and sequencing of these new immune therapies and their integration into clinical MM management may depend on the underlying immune status, in turn impacted by host, tumor, and environmental features. Immune therapies carry the potential to achieve durable unmaintained responses and cures in MM.

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Plasma cell numbers decrease in bone marrow of old patients

et al. 2014

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The BM is well understood to play a key role in plasma cell homing and survival in mice. In humans, BM plasma cells and their functions are less well characterized. In this study, we used paired bone biopsies from the femur shaft and blood samples from persons of different ages to analyze age-related changes of plasma and memory B cells. Our results demonstrated that plasma cells were mainly located in the BM, while a higher percentage of memory B cells was in the peripheral blood than in the BM. The frequency of plasma and memory B cells from both sources decreased with age, while immature and naïve B cells were unaffected. An age-related decline of tetanus-and diphtheria-specific BM plasma cells was observed, whereas influenza A-and cytomegalovirus-specific BM plasma cells were not affected. With the exception of cytomegalovirus, peripheral antibody concentrations correlated with BM plasma cells of the same specificity, but were independent of antigen-specific peripheral blood memory B cells. Our results demonstrate that the BM houses decreased numbers of plasma cells in old age. The number of cells of certain specificity may reflect the number and time point of previous antigen encounters and intrinsic age-related changes in the BM. Keywords: Aging r Bone marrow r Memory B cells r Plasma cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionImmunologic memory is a hallmark of the adaptive immune system. Previous studies indicate that the BM is a secondary lymphoid organ and a major reservoir of memory CD4 + and CD8 + T cells + population were significantly decreased in BMMCs in the older age group, whereas the percentages of immature and naïve B cells were similar in both age groups ( Fig. 2A and C). Similar results to BMMCs were observed for PBMCs (Fig. 2B and D). Functional characterization of BM plasma cells and PB memory B cells in old ageNext, we analyzed the impact of aging on the frequency of antigenspecific BM plasma cells, PB-derived memory B cells as well as on peripheral antibody concentrations. Tetanus and diphtheria represent antigens against which most of our donors had been immunized in the past, but for which natural exposure is unlikely. In contrast, influenza A is a pathogen which is encountered frequently by natural exposure and/or vaccination. Cytomegalovirus (CMV) is a persistent virus which during latent infection chronically stimulates immune responses. The frequencies of tetanus-and diphtheria-specific BM plasma cells correlated negatively with age ( Fig. 3A). In contrast, no correlation between influenza A-specific BM plasma cells and age was observed. The frequency of CMV-specific BM plasma cells did not change with age in persons with a positive serotype.To assess age-related alterations of PB-derived memory B cells of a certain specificity, isolated PBMCs were preactivated with pokeweed mitogen, ODN2006, and Staphylococcus aureus Cowan to stimulate antibody production. The percentage of antibodysecreting ce...

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Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory

Cited by 158 publications

References 44 publications

Immunological memories of the bone marrow

Immunological memories of the bone marrow

The immune system in multiple myeloma and precursor states: Lessons and implications for immunotherapy and interception

Plasma cell numbers decrease in bone marrow of old patients

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