Lymphotoxin-alpha contributes to lymphangiogenesis

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
Blood (Impact Factor: 10.45). 09/2010; 116(12):2173-82. DOI: 10.1182/blood-2009-12-256065
Source: PubMed


Lymphotoxin-α (LTα), lymphotoxin-β (LTβ), and tumor necrosis factor-α (TNFα) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LTα also contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LTα(-/-) mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LTβ(-/-) mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type (WT) or LTα(-/-) mice, as did the skin draining immunization sites of LTβ(-/-) mice. Macrophages, B cells, and T cells, known sources of LT and TNFα, were apparent in the skin surrounding the immunization sites as were LTα, LTβ, and TNFα mRNAs. Ectopic expression of LTα led to the development of LYVE-1 and Prox1-positive lymphatic vessels within tertiary lymphoid organs (TLOs). Quantification of pancreatic lymphatic vessel density in RIPLTαLTβ(-/-) and WT mice revealed that LTα was sufficient for inducing lymphangiogenesis and that LTβ was not required for this process. Kidneys of inducible LTα transgenic mice developed lymphatic vessels before the appearance of obvious TLOs. These data indicate that LTα plays a significant role in lymphatic vessel function and in inflammation-associated lymphangiogenesis.

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Available from: Peter Baluk, Sep 11, 2015
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    • "The lymphatic endothelial cells are an important source of sphingosine-1-phosphate that elicits lymphocytes to leave the parenchyma and enter the sinuses (114). Whether LTβR signaling is crucial for lymphatic function is less clear, although defects in lymphatic function were observed in LT-deficient mice (115). "
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    ABSTRACT: Lymphoid organs are meeting zones where lymphocytes come together and encounter antigens present in the blood and lymph or as delivered by cells migrating from the draining tissue bed. The exquisite efficiency of this process relies heavily on highly specialized anatomy to direct and position the various players. Gated entry and exit control access to these theaters and reticular networks and associated chemokines guide cells into the proper sections. Lymphoid tissues are remarkably plastic, being able to expand dramatically and then involute upon resolution of the danger. All of the reticular scaffolds and vascular and lymphatic components adapt accordingly. As such, the lymph node (LN) is a wonderful example of a physiologic remodeling process and is potentially a guide to study such elements in pathological settings such as fibrosis, chronic infection, and tumor metastasis. The lymphotoxin/LIGHT axis delivers critical differentiation signals that direct and hone differentiation of both reticular networks and the vasculature. Considerable progress has been made recently in understanding the mesenchymal differentiation pathways leading to these specialized networks and in the remodeling that occurs in reactive LNs. In this article, we will review some new advances in the area in terms of developmental, differentiation, and maintenance events mediated by this axis.
    Frontiers in Immunology 02/2014; 5:47. DOI:10.3389/fimmu.2014.00047
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    • "During the ontogeny of TLO in peripheral tissues, lymphatic vessels (i.e., PNAd+, MAdCAM-1+, LYVE-1+, and/or Prox-1+ HEV) and disorganized clusters of APC and infiltrating lymphocytes appear in advance of canonical mature lymphoid organ architecture characterized by B cell follicular regions (19, 71). Signals that instigate the diffuse-to-organized structural transition of TLO may be provided by cognate T cell recognition of relevant target cell populations within nascent TLO (15, 72). "
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    ABSTRACT: Ectopic lymphoid tissue, also known as tertiary lymphoid organs (TLO) develop adaptively within sites of chronic tissue inflammation, thereby allowing the host to efficiently crossprime specific immune effector cells within sites of disease. Recent evidence suggests that the presence of TLO in the tumor microenvironment (TME) predicts better overall survival. We will discuss the relevance of extranodal T cell priming within the TME as a means to effectively promote anti-tumor immunity and the strategic use of dendritic cell (DC)-based therapies to reinforce this clinically preferred process in the cancer-bearing host.
    Frontiers in Immunology 11/2013; 4:388. DOI:10.3389/fimmu.2013.00388
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    • "Impaired signaling through LTβR reduces spleen CXCL13, CCL19 and CCL21 levels, leading to disorganization of white pulp areas [21]. LTα also contributes to lymphangiogenesis [22]. "
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    ABSTRACT: The role of p110δ PI3K in lymphoid cells has been studied extensively, showing its importance in immune cell differentiation, activation and development. Altered T cell localization in p110δ-deficient mouse spleen suggested a role for p110δ in non-hematopoietic stromal cells, which maintain hematopoietic cell segregation. We tested this hypothesis using p110δ(WT/WT) mouse bone marrow to reconstitute lethally irradiated p110δ(WT/WT) or p110δ(D910A/D910A) (which express catalytically inactive p110δ) recipients, and studied localization, number and percentage of hematopoietic cell subsets in spleen and lymph nodes, in homeostatic conditions and after antigen stimulation. These analyses showed diffuse T cell areas in p110δ(D910A/D910A) and in reconstituted p110δ(D910A/D910A) mice in homeostatic conditions. In these mice, spleen CD4(+) and CD8(+) T cell numbers did not increase in response to antigen, suggesting that a p110δ(D910A/D910A) stroma defect impedes correct T cell response. FACS analysis of spleen stromal cell populations showed a decrease in the percentage of gp38(-)CD31(+) cells in p110δ(D910A/D910A) mice. qRT-PCR studies detected p110δ mRNA expression in p110δ(WT/WT) spleen gp38(-)CD31(+) and gp38(+)CD31(+) subsets, which was reduced in p110δ(D910A/D910A) spleen. Lack of p110δ activity in these cell populations correlated with lower LTβR, CCL19 and CCL21 mRNA levels; these molecules participate in T cell localization to specific spleen areas. Our results could explain the lower T cell numbers and more diffuse T cell areas found in p110δ(D910A/D910A) mouse spleen, as well as the lower T cell expansion after antigen stimulation in p110δ(D910A/D910A) compared with p110δ(WT/WT) mice.
    PLoS ONE 08/2013; 8(8):e72960. DOI:10.1371/journal.pone.0072960 · 3.23 Impact Factor
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