CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

Jung, Yong Woo; Kim, Hyun Gyung; Perry, Curtis J.; Kaech, Susan M.

doi:10.1073/pnas.1602899113

Cited by 52 publications

(47 citation statements)

References 41 publications

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“…In the BM, around 30% of the CD8 + memory cells express CD69 and around 70% do not express CCR7 (data not shown). It has been proposed that CD69 marks “tissue‐resident” memory T cells , and that CCR7 − CD8 + memory T cells are maintained by IL‐15 induced proliferation . The present analysis shows that both CD69 + and CD69 − and also CCR7 + and CCR7 − CD8 + memory T cells of the BM are resting and resident.…”

Section: Resultssupporting

confidence: 53%

“…in the apparent absence of antigen. The current view is that numbers of CD8 + memory T cells are maintained by homeostatic proliferation, a proliferation induced by cytokines like interleukin‐15 (IL‐15) compensating a gradual loss of memory cells by apoptosis . This view is based on analysis of the proliferation of CD8 + memory T cells, isolated from the spleen, labeled with CFSE and adoptively transferred from one mouse to another.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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It is current belief that numbers of CD8+ memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here, we compare the proliferation of CD8+ memory T lymphocytes, generated by natural infections and by intentional immunization, in spleen and bone marrow (BM). Fifty percent of CD8+ memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8+ memory T lymphocytes are maintained by proliferation. The numbers of CD8+ memory T lymphocytes in the BM, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8+ memory T cells, blocked by FTY720, showing that BM is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation.

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Section: Resultssupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…Exploring the role of cytokines and trophic factors that drive memory differentiation has also led to an increasing appreciation for the importance of tissue localization of effector T cells in their eventual differentiation to memory (7, 52). Perhaps the most prevalent concept stems from the expression of CD62L by central memory T cells with stem-like properties that sustain long-term memory (32, 53, 54).…”

Section: Discussionmentioning

confidence: 99%

Eomesodermin driven IL-10 production in effector CD8+ T cells promotes a memory phenotype

Reiser

Sadashivaiah

Furusawa

et al. 2019

Cellular Immunology

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CD8+ T cell differentiation is controlled by the transcription factors T-bet and Eomesodermin, in concert with the cytokines IL-2, IL-10 and IL-12. Among these pathways, the mechanisms by which T-box proteins and IL-10 interact to promote a memory T cell fate remain poorly understood. Here, we show that Eomes and IL-10 drive a central memory phenotype in murine CD8+ T cells. Eomes expression led to increased IL-10 expression by the effector CD8+ T cells themselves as well as an increase in the level of the lymph node homing selectin CD62L. Furthermore, exposure of effector CD8+ T cells to IL-10 maintained CD62L expression levels in culture. Thus, Eomes promotes a step-wise transition of effector T cells towards a memory phenotype, synergizing with IL-10 to enhance the expression of CD62L. The early augmentation of lymph node homing markers by Eomes may facilitate the retention of effector T cells in the relatively low inflammatory milieu of the secondary lymphoid organs that promotes central memory development.

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“…Jung et al. showed that the opposite is in fact true and that IL‐7 is important for CD8 memory T cells in the spleen, whereas IL‐15 plays a major role in the BM . Furthermore, in human BM most CD8 memory T cells localize close to IL‐15 producing cells .…”

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confidence: 99%

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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CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

Cited by 52 publications

References 41 publications

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

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

Eomesodermin driven IL-10 production in effector CD8+ T cells promotes a memory phenotype

Maintenance of memory CD8 T cells: Divided over division

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CCR7 expression alters memory CD8 T-cell homeostasis by regulating occupancy in IL-7– and IL-15–dependent niches

Cited by 52 publications

References 41 publications

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

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

Eomesodermin driven IL-10 production in effector CD8+ T cells promotes a memory phenotype

Maintenance of memory CD8 T cells: Divided over division

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

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