Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning

Pham, Trung H.M.; Bałuk, Peter; Xu, Ying; Grigorova, Irina; Bankovich, Alexander J.; Pappu, Rajita; Coughlin, Shaun R.; McDonald, Donald M.; Schwab, Susan R.; Cyster, Jason G.

doi:10.1083/jcb1877oia15

Cited by 102 publications

(164 citation statements)

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“…Cellular egress from PP into mesenteric lymph appears to occur mostly from the interfollicular region, where the absorbing lymphatic peripheral vessels form a dense network (49). One possible explanation for the apparently CCR7-independent accumulation of migratory CD103 2 DCs in MLN is thus that the entry of these cells from the PP into the mesenteric lymphatic vessels instead is dependent on signals that govern leukocyte egress from the PP (50,51).…”

Section: Discussionmentioning

confidence: 99%

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

Hägerbrand

Westlund

Agace

et al. 2015

The Journal of Immunology

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Intestinal homeostasis and induction of systemic tolerance to fed Ags (i.e., oral tolerance) rely on the steady-state migration of small intestinal lamina propria dendritic cells (DCs) into draining mesenteric lymph nodes (MLN). The majority of these migratory DCs express the α integrin chain CD103, and in this study we demonstrate that the steady-state mobilization of CD103+ DCs into the MLN is in part governed by the IL-1R family/TLR signaling adaptor molecule MyD88. Similar to mice with complete MyD88 deficiency, specific deletion of MyD88 in DCs resulted in a 50–60% reduction in short-term accumulation of both CD103+CD11b+ and CD103+CD11b− DCs in the MLN. DC migration was independent of caspase-1, which is responsible for the inflammasome-dependent proteolytic activation of IL-1 cytokine family members, and was not affected by treatment with broad-spectrum antibiotics. Consistent with the latter finding, the proportion and phenotypic composition of DCs were similar in mesenteric lymph from germ-free and conventionally housed mice. Although TNF-α was required for CD103+ DC migration to the MLN after oral administration of the TLR7 agonist R848, it was not required for the steady-state migration of these cells. Similarly, TLR signaling through the adaptor molecule Toll/IL-1R domain-containing adapter inducing IFN-β and downstream production of type I IFN were not required for steady-state CD103+ DC migration. Taken together, our results demonstrate that MyD88 signaling in DCs, independently of the microbiota and TNF-α, is required for optimal steady-state migration of small intestinal lamina propria CD103+ DCs into the MLN.

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Section: Discussionmentioning

confidence: 99%

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

Hägerbrand

Westlund

Agace

et al. 2015

The Journal of Immunology

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“…PLN (inguinal and axillary) and MLN were isolated and enzymatically digested as previously described [35]. Briefly, lymph nodes were minced into small pieces and added into RPMI 1640 containing 100 μg/mL DNase I and 0.025 mg/mL liberase TM and 2% FCS.…”

Section: Cellsmentioning

confidence: 99%

“…The expression of CD73 on human ECs was determined using with 4G4 and Alexa 488 second-stage reagent. The multicolor immunostainings of mouse MLN and PLN (inguinal) were performed as described [35]. The stromal cells were gated for alive (7 AAD-negative), CD45.2-PerCP-Cy5.5 negative cells, and analyzed for podoplanin-PE-Cy7, CD31-allophycocyanin, and CD73-PE.…”

Section: Antibodies and Immunostainingsmentioning

confidence: 99%

“…The ECs were separated to BEC and LEC subsets using human "Do-itYourself" EasySep immunomagnetic kit (Stem Cell Technologies) and mouse anti-podoplanin mAb (a LEC-specific marker; Acris Antibodies GmbH, Herford, Germany). PLN (inguinal and axillary) and MLN were isolated and enzymatically digested as previously described [35]. Briefly, lymph nodes were minced into small pieces and added into RPMI 1640 containing 100 μg/mL DNase I and 0.025 mg/mL liberase TM and 2% FCS.…”

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confidence: 99%

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Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

et al. 2014

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CD73/ecto-5 -nucleotidase is a key enzyme in the regulation of purinergic signaling and inflammatory reactions. It hydrolyzes extracellular AMP into adenosine, which dampens immune cell activation, and reduces leukocyte trafficking. By comparing CD73 expression and function in mononuclear and endothelial cells (ECs) of blood and lymph, we show that extracellular purines and CD73 activity have differential effects in these two vascular systems. We found that CD8-positive T lymphocytes and CD19-positive B lymphocytes in human lymph expressed high levels of CD73 and other purinergic enzymes and adenosine receptors. Soluble CD73 was less abundant in human lymph than in serum, whereas CD73 activity was higher in afferent lymphatic ECs than in blood ECs. Adenosine signaling improved barrier function and induced sprouting of human blood, but not lymphatic, ECs in vitro. Similarly, using CD73-deficient mice we found that CD73 controls only blood vascular permeability at selected lymphoid organs under physiological conditions. Thus, both vascular and lymphatic arms of the immune system synthesize the components of purinergic signaling system, but surprisingly they use CD73 differentially to control endothelial permeability and sprouting.Keywords: adenosine r endothelial cells r lymphatics r permeability r purinergic signaling See accompanying Commentary by Sidibé and Imhof.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPurinergic signaling plays a central role in controlling inflammation [1][2][3][4][5][6][7]. ATP and other purines are released to the cell Correspondence: Dr. Marko Salmi e-mail: marko.salmi@utu.fi exterior from intracellular pools both under physiological and pathological conditions via diverse pathways including exocytosis, specific channels, transporters, as well as cell death. On the cell surface extracellular ATP is sequentially hydrolyzed to ADP, AMP, * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 562-573 Molecular immunology 563 and adenosine through the action of specific ectonucleotidases [5]. Each of these purines can then bind to specific cell surface receptors and trigger intracellular signaling responses. Notably, ATP and ADP are proinflammatory and prothrombotic molecules, whereas adenosine usually exerts strong anti-inflammatory effects [4]. One rate-limiting enzyme in the purinergic signaling cascade is CD73/ecto-5 -nucleotidase, which converts AMP into adenosine [8,9]. CD73 is expressed on small subsets of lymphocytes, most notably on Treg cells, where it is crucial for the immunesuppressing functions [10]. CD73 is also present on endothelial cells (ECs). It is synthesized both on blood ECs (BECs) and lymphatic ECs (LECs). The role of CD73 on BECs in controlling vascular permeability and leukocyte trafficking is relatively well understood [11][12][13][14][15][16][17], but the function of lymphatic CD73 remains co...

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“…Lymphocyte entry into LNs from the blood occurs at high endothelial venules and is chiefly mediated by interactions between CC chemokine receptor (CCR)7 on the T-cell, and CCL19 and CCL21 expressed by the specialized stromal component, the fibroblastic reticular cell (FRC) (1)(2)(3). Lymphocyte egress from LNs occurs at lymphatic sinuses and requires the sphingosine-1 phosphate receptor-1 (S1PR1) (4,5). Previous studies have demonstrated that S1PR1, at least in part, operates to overcome the CCR7-mediated retention signal to allow egress of naïve T cells into the lymph (5,6), and it has been suggested that a similar balance of signals controls the egress of activated T cells.…”

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confidence: 99%

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells

Denton

Roberts

Linterman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

117

116

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Fibroblastic reticular cells (FRCs), through their expression of CC chemokine ligand (CCL)19 and CCL21, attract and retain T cells in lymph nodes (LNs), but whether this function applies to both resting and activated T cells has not been examined. Here we describe a model for conditionally depleting FRCs from LNs based on their expression of the diphtheria toxin receptor (DTR) directed by the gene encoding fibroblast activation protein-α (FAP). As expected, depleting FAP + FRCs causes the loss of naïve T cells, B cells, and dendritic cells from LNs, and this loss decreases the magnitude of the B-and T-cell responses to a subsequent infection with influenza A virus. In contrast, depleting FAP + FRCs during an ongoing influenza infection does not diminish the number or continued response of activated T and B cells in the draining LNs, despite still resulting in the loss of naïve T cells. Therefore, different rules govern the LN trafficking of resting and activated T cells; once a T cell is engaged in antigen-specific clonal expansion, its retention no longer depends on FRCs or their chemokines, CCL19 and CCL21. Our findings suggest that activated T cells remain in the LN because they down-regulate the expression of the sphingosine-1 phosphate receptor-1, which mediates the exit of lymphocytes from secondary lymphoid organs. Therefore, LN retention of naïve lymphocytes and the initiation of an immune response depend on FRCs, but is an FRC independent and possibly cell-autonomous response of activated T cells, which allows the magnitude of clonal expansion to determine LN egress. viral infection | T-cell migration | lymph node stroma

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Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning

Cited by 102 publications

References 1 publication

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells

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Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning

Cited by 102 publications

References 1 publication

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

MyD88 Signaling Regulates Steady-State Migration of Intestinal CD103+ Dendritic Cells Independently of TNF-α and the Gut Microbiota

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 + T cells

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Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8 ⁺ T cells