Serial Transfer of Single-Cell-Derived Immunocompetence Reveals Stemness of CD8+ Central Memory T Cells

Graef, Patricia; Buchholz, Veit R.; Stemberger, Christian; Floßdorf, Michael; Henkel, Lynette; Schiemann, Matthias; Drexler, Ingo; Höfer, Thomas; Riddell, Stanley R.; Busch, Dirk H.

doi:10.1016/j.immuni.2014.05.018

Cited by 285 publications

(271 citation statements)

References 70 publications

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“…In response to antigen-induced inflammation, thymic naïve T cells migrate from thymus to targeted tissues and are activated to become effector and memory T cells. Of note, the CD8 + memory T cells seed in bone marrow as adult stem cells after inflammation [45,46]. In our study, naïve T cells and central memory T cells were attracted to the bone marrow of Nestin-Cre; Wls c/c mice.…”

Section: Discussionmentioning

confidence: 49%

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

et al. 2015

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Osteoblasts and perivascular stromal cells constitute essential niches for HSC selfrenewal and maintenance in the bone marrow. Wnt signaling is important to maintain HSC integrity. However, the paracrine role of Wnt proteins in osteoblasts-supported HSC maintenance and differentiation remains unclear. Here, we investigated hematopoiesis in mice with Wntless (Wls) deficiency in osteoblasts or Nestin-positive mesenchymal progenitor cells, which presumptively block Wnt secretion in osteoblasts. We detected defective B-cell lymphopoiesis and abnormal T-cell infiltration in the bone marrow of Wls mutant mice. Notably, no impact on HSC frequency and repopulation in the bone marrow was observed with the loss of osteoblastic Wls. Our findings revealed a supportive role of Wnts in osteoblasts-regulated B-cell lymphopoiesis. They also suggest a preferential niche role of osteoblastic Wnts for lymphoid cells rather than HSCs, providing new clues for the molecular nature of distinct niches occupied by different hematopoietic cells.Keywords: B cell r HSC maintenance r Osteoblast r T-cell infiltration r Wntless Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHSCs that periodically generate all hematopoietic lineages are mostly stored in vascular or endosteal niches in the bone marrow [1]. Vascular niches consist of sinusoidal endothelium cells [2][3][4] whereas endosteal niches are mainly composed of osteoblasts [5,6]. These niche cells are important to regulate HSCs self-renewal and maintenance. Recent evidence also reveals that perivascular Nestin + mesenchymal progenitor cells form a supportive niche for HSCs [3,7,8]. In addition, studies from Dr. Morrison suggest that HSCs mainly reside in the perivascular niches whereas the early lymphoid progenitor cells prefer to locate at endosteal niches [9,10].Correspondence: Dr. Xizhi Guo e-mail: xzguo2005@sjtu.edu.cn; zjyao@sjtu.edu.cnCompelling evidence reveals that Wnt signaling is an important regulator for HSCs integrity and function. Wnt proteins, which consist of 19 members in mammals, could be transduced through canonical or noncanonical signaling pathways [11]. β-Catenin is the key and obligatory mediator of canonical Wnt signaling. Stabilized β-catenin expression expands the pool of HSCs and leads to deficiency in HSCs repopulation capacity [12,13]. Conversely, deletion of β-catenin or Wnt3a leads to defective HSCs long-term maintenance [14,15]. Nevertheless, several lines of evidence also indicate that β-catenin is dispensable for HSCs maintenance [16,17]. On the other hand, inhibition of environmental canonical Wnt signaling in osteoblasts impairs HSCs self-renewal and quiescence [18]. Collectively, canonical Wnt signaling is revealed to * These authors contributed equally to this work. regulate HSCs self-renewal in a dosage-dependent manner [19]. In addition, noncanonical Wnt signaling is also reported to sustain HSCs maintenance and aging [20,21]. Osteoblasts also support B-cell commitment an...

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Section: Discussionmentioning

confidence: 49%

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

et al. 2015

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“…However, elegant in vivo approaches using adoptive transfer systems of single murine CD8 + memory cells (Gerlach et al, 2013a;Graef et al, 2014) also argue in favor of a linear differentiation model. As similar experiments have not been conducted for CD4 + cells yet and are impossible in the human system, our data represent new insights into this topic.…”

Section: Discussionmentioning

confidence: 99%

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

Durek¹,

Nordström²,

Gasparoni³

et al. 2016

Immunity

181

192

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“…Several studies have provided evidence that the quality of the T cell response against pathogens could be used as a correlate of protection, and the cytokine polyfunctionality of the CD8 + T cells is considered as an important parameter to determine this (26). Cytokine polyfunctionality of T cells is an important characteristic of the so-called central-memory T cells, and several studies indicated that the expansion potential of central-memory T cells is superior compared with effector-memory T cells in regard to expansion (27)(28)(29)(30)(31). Autocrine IL-2 production is part of the polyfunctional central-memory T cell profile, and our study now provides direct evidence that autocrine IL-2 production contributes to a greater expansion capacity of CD8 + T cells.…”

Section: Discussionmentioning

confidence: 99%

The Quantity of Autocrine IL-2 Governs the Expansion Potential of CD8+ T Cells

Redeker

Welten

Baert

et al. 2015

The Journal of Immunology

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Adequate responsiveness of CD8+ T cell populations is of utmost importance for the efficacy of many vaccines and immunotherapeutic strategies against intracellular pathogens and cancer. In this study, we show in mouse models that the relative number of IL-2–producing cells within Ag-specific CD8+ T cell populations predicts the population expansion capacity upon challenge. We further demonstrate that IL-2 producers constitute the best responding subset. Notably, we show that elevated production of IL-2 by CD8+ T cells results in concomitant improved population expansion capacity and immunity. The amount of IL-2 produced on a per-cell basis essentially connects directly to the superior CD8+ T cell population expansion. Together, our findings identified that autocrine IL-2 production operates in a dose-dependent fashion to facilitate the expansion potential of Ag-specific CD8+ T cell populations, which may instigate ways to augment therapies depending on fit CD8+ T cells.

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Serial Transfer of Single-Cell-Derived Immunocompetence Reveals Stemness of CD8+ Central Memory T Cells

Cited by 285 publications

References 70 publications

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

Ablation of Wntless in endosteal niches impairs lymphopoiesis rather than HSCs maintenance

Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development

The Quantity of Autocrine IL-2 Governs the Expansion Potential of CD8+ T Cells

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