T Lymphocytes Negatively Regulate Lymph Node Lymphatic Vessel Formation

Abstract

Lymph node lymphatic vessels (LNLVs) serve as a conduit to drain antigens from peripheral tissues to within the lymph nodes. LNLV density is known to be positively regulated by vascular endothelial growth factors secreted by B cells, macrophages, and dendritic cells (DCs). Here, we show that LNLV formation was negatively regulated by T cells. In both steady and inflammatory states, the density of LNLVs was increased in the absence of T cells but decreased when T cells were restored. Interferon-γ secretion by T cells suppressed lymphatic-specific genes in lymphatic endothelial cells and consequently caused marked reduction in LNLV formation. When T cells were depleted, recruitment of antigen-carrying DCs to LNs was augmented, reflecting a compensatory mechanism for antigen presentation to T cells through increased LNLVs. Thus, T cells maintain the homeostatic balance of LNLV density through a negative paracrine action of interferon-γ.

Obesity, But Not High Fat Diet, Impairs Lymphatic Function

“…50,51 Finally, T cell-derived cytokines including IFN-γ, IL-4 and IL-13 have been shown to directly inhibit lymphangiogenesis. 46,52 Consistent with previous studies in obese mice and patients, 26 we noted a marked increase in VEGF-C expression in tissues and serum harvested from obese HFD-fed C57BL/6J mice. This effect has a key role on glucose homeostasis in obesity by regulating macrophage infiltration and differentiation.…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Toll-like receptor (TLR)-4 is highly expressed in LECs and contributes to lipopolysaccharide (LPS)-induced lymphangiogenesis by chemotactic recruitment of macrophages ). Notably, a recent study showed that lymph nodes in athymic nude mice have excessive lymphatic vessels and that interferon-g released by T lymphocytes negatively regulates lymph-node lymphatic vessel formation by suppressing key lymphatic molecules (Kataru et al 2011). Importantly, lymphatic vessels can perform functions beyond passive conduits for immune response.…”

Apolipoprotein A-I Limits the Negative Effect of Tumor Necrosis Factor on Lymphangiogenesis

“…28 On the other hand, the loss of Prox-1 activity results in defective lymphangiogenesis. 13,14 In a murine contact hypersensitivity model, downregulation of Prox-1 is inversely correlated with local TNF and interferon-γ production. 29 Furthermore, mice heterozygous for a mutation that inactivates Prox-1 exhibit features of leaky lymphatic vessels and are prone to develop obesity and inflammation.…”

“…The loss of the transcriptional activity of Prox-1 has previously been associated with suppression of LEC tube formation 13 and lymphatic sprouting of TD rings, 14 underscoring its fundamental role for determining the lymphatic phenotype. This was confirmed as shown in Figure 4A, which shows that Prox-1 mRNA levels are decreased 2.3-fold when LECs are incubated with TNF (P<0.05 compared with control).…”