Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals

Zou, Linhua; Barnett, Brian B.; Safah, Hana; LaRussa, Vincent F.; Evdemon-Hogan, Melina; Mottram, Peter; Wei, Shuang; David, Odile; Curiel, Tyler J.; Zou, Weiping

doi:10.1158/0008-5472.can-04-1987

Cited by 400 publications

(373 citation statements)

References 39 publications

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“…CXCL12 can induce chemotaxis of Tregs. 22 Correlation between Treg infiltration and CXCL12 expression has been found in cervical cancer. 23 Classical Tregs inhibit T cells in lymphoid organs.…”

Section: Acquisition Of Metastatic Potential In Primary Tumorsmentioning

confidence: 99%

“…These changes may mobilize Tregs from the bone-marrow reservoir to the periphery. 22 PRIMARY TUMORS AFFECT PREMETASTATIC TISSUES Although metastatic outgrowth of tumor cells is abrogated in CD4-null conditions, including the RAG knockout, which attenuated EGF receptor-mediated activation of metastatic potential of primary tumor cells, we still do not know the mechanisms of the last three steps in metastasis: extravasation, recruitment and regrowth in the lungs. 24 Less than 1% of recruited tumor cells appear to achieve regrowth.…”

Section: Acquisition Of Metastatic Potential In Primary Tumorsmentioning

confidence: 99%

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Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

Maru

2010

Cell Mol Immunol

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Accumulating evidence suggests that Toll-like receptor 4 (TLR4), a sensor for danger signals, is expressed not only in immune cells, but also in resident epithelial cells, and appears to participate in tissue homeostasis. To explain the premetastatic microenvironment created by the newly discovered endogenous TLR4 ligands, I propose a hypothesis of homeostatic inflammation that includes the classical danger hypothesis.

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Section: Acquisition Of Metastatic Potential In Primary Tumorsmentioning

confidence: 99%

Section: Acquisition Of Metastatic Potential In Primary Tumorsmentioning

confidence: 99%

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

Maru

2010

Cell Mol Immunol

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“…It has been reported that CD4 ϩ CD25 ϩ or FoxP3 ϩ Tregs express CCR4, CCR5, CCR7, CCR8, CCR10, CXCR4, and CXCR5 and L-selectin, E-selectin, and P-selectin ligands (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). CD103 ϩ Tregs express effector/memory-type trafficking receptors, and CD103 Ϫ Tregs express lymphoid tissue homing receptors (20).…”

mentioning

confidence: 99%

FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues

Lee

Kang

Kim

2007

The Journal of Immunology

113

128

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Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3+ T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3+ T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4+ T cells as well as unique to the FoxP3+ cell lineage. In the thymus, precursors of FoxP3+ cells undergo the first trafficking receptor switch (CCR8/CCR9→CXCR4→CCR7), generating mostly homogeneous CD62L+CCR7+CXCR4lowFoxP3+ T cells. CXCR4 expression is regained in FoxP3+ thymic emigrants in the periphery. Consistent with this switch, recent FoxP3+ thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3+ thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3+ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3+ and FoxP3− T cell populations is that FoxP3+ T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3− T cells, generating FoxP3+ T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.

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“…Therefore, Treg cells appear not to directly stimulate the differentiation of hematopoietic progenitors into B cells. In contrast to the lack of effect of Treg cells, the addition of activated CD4 + [12]. We found that the K/Bsf BM harbored more CD4 + T cells than the K/B BM, and most of them retained memory/activated phenotypes (data not shown).…”

Section: Treg Cells Protect B Lymphopoiesis By Controlling the Supprementioning

confidence: 73%

Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

et al. 2014

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Foxp3 + Treg cells are crucial for maintaining T-cell homeostasis, but their role in B-cell homeostasis remains unclear. Here, we found that Foxp3 mutant scurfy mice had fewer B-lineage cells and progenitors, including common lymphoid progenitors and lymphoidprimed multipotent progenitors, but higher myeloid-lineage cell numbers in BM compared with WT littermates. Homeostasis within the HSC compartment was also compromised with apparent expansion of long-and short-term HSCs. This abnormality was due to the lack of Treg cells, but not to the Treg-cell extrinsic functions of Foxp3 or cellautonomous defects. Among cytokines enriched in the BM of scurfy mice, IFN-γ affected only B lymphopoiesis, but GM-CSF, TNF, and IL-6 collectively promoted granulopoiesis at the expense of B lymphopoiesis. Neutralization of these three cytokines reversed the hematopoietic defects on early B-cell progenitors in scurfy mice. Treg cells ensured B lymphopoiesis by reducing the production of these cytokines by effector T cells, but not by directly affecting B lymphopoiesis. These results suggest that Treg cells occupy an important niche in the BM to protect B-lineage progenitor cells from excessive exposure to a lymphopoiesis-regulating milieu.Keywords: B lymphopoiesis r Foxp3 r Granulopoietins r Hematopoiesis r Regulatory T cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction CD4 + Foxp3 + Treg cells are essential for maintaining immune homeostasis, as evidenced by the severe autoimmune lymphoproliferative disease observed in Treg-cell-deficient mice and humans [1,2]. Treg cells were initially identified in the secondary lymphoid tissues where they suppress the initial priming and Correspondence: Prof. Jeehee Youn e-mail: jhyoun@hanyang.ac.kr effector differentiation of autoreactive T cells [3]. They function by directly suppressing T cells and/or interacting with DCs to limit their ability to prime T cells effectively [4,5]. In addition to their constitutive presence in secondary lymphoid tissues, Treg cells have been found in several nonlymphoid sites, such as mucosal tissue, skin, liver, and lung, during inflammation as well as in steady-state conditions [6][7][8][9][10]. These Treg cells appear to regulate * These authors contributed equally to this work. * * These senior authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 168Sunghoon Kim et al. Eur. J. Immunol. 2015. 45: 167-179 tissue-tropic autoimmunity and inflammation, and alter pathogen clearance during peripheral infection. A diverse array of adhesion molecules and chemokine receptors that are expressed on Treg cells seem to license them to migrate to peripheral tissues. A fraction of Treg cells have been shown to express the BM homing receptor CXCR4 [11], suggesting the existence of a niche for Treg cells in the BM. Indeed, there are studies showing that healthy human BM contains a substantial number of Treg cells that traffic via CXC...

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Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals

Cited by 400 publications

References 39 publications

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues

Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

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Bone Marrow Is a Reservoir for CD4+CD25+ Regulatory T Cells that Traffic through CXCL12/CXCR4 Signals

Cited by 400 publications

References 39 publications

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues

Foxp3+ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow

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Foxp3⁺ regulatory T cells ensure B lymphopoiesis by inhibiting the granulopoietic activity of effector T cells in mouse bone marrow