The Lymphotoxin Pathway: Beyond Lymph Node Development

Abstract

The first studies of mice deficient in lymphotoxin-alpha (LTalpha), LTbeta and LTbetaR revealed the seminal discovery that the LTbetaR signaling is critical for the development of lymph nodes and Peyer's patches during embryogenesis. Since these initial findings, it is increasingly appreciated that signaling through the lymphotoxin-beta receptor (LTbetaR) plays a key role in numerous biological processes in the adult animal, including the maintenance of specialized stromal cell types and the homeostatic control of chemokine expression within the lymphoid tissues. A major focus of our laboratory is to understand the relevance of LTbetaR signaling in initiating immune responses both dependent and independent of its role in maintaining the organization of lymphoid tissues. This review will therefore explore new possibilities for how this complex pathway regulates humoral and cellular immunity.

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

“…In addition to TNF receptors, LT binds to membrane-bound LT␤ (LT␣ 1 ␤ 2 ), and this heterotrimer (membrane LT) is the ligand for the membrane-bound LT␤ receptor (LT␤R). Membrane LT is expressed by activated T, B, and NK cells, and the LT␤R is expressed in nonlymphoid tissues and dendritic cells (40,80). Thus, lack of LT may influence the ability of the LT␤R to direct inflammatory cell responses in adipose tissue.…”

“…However, with the recognition of T cell and B cell involvement in obesity and insulin resistance, it is important to reflect on proteins that are able to modulate lymphocyte biology (5,27,35,47,72,79). Here, we focus on the role in obesity of lymphotoxin-␣ (LT␣), a key cytokine involved in T cell and B cell differentiation, homing, and activation (12,40,78).…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…A major role of LT in inflammation was first implied by its ability to activate endothelial cells in vitro to express adhesion molecules (for example, V-CAM, I-CAM) (Pober, 1987;Pober et al, 1987;Cavender et al, 1989), to regulate expression of homeostatic chemokines (for example, CXCL13, CCL19, CCL21) (Ansel et al, 2000;McCarthy et al, 2006) and to induce a variety of pro-and anti-inflammatory chemokines (for example, CCL5, CCL2, CXCL10) (Cuff et al, 1998(Cuff et al, , 1999.…”

Soluble lymphotoxin is an important effector molecule in GVHD and GVL

“…12 The membrane-bound heterotrimeric forms signal through the LT␤ receptor, expressed on stroma, epithelium, and antigen-presenting cells, and this signaling does not directly induce apoptosis. 30 To eliminate the possibility that LT␣␤ heterotrimers were playing a role in GVHD mortality, we performed transplantations using B6.Ltb Ϫ/Ϫ donors, which lack only the membrane-bound forms of the molecule. In both the B63B6D2F 1 ( Figure 3B) and B63BALB/c ( Figure 3C) models of GVHD, the protective effect seen when grafts lacked LT␣ was not demonstrated when grafts were deficient only in LT␤.…”