Description
Lymphotoxin alpha (LT-α), and Lymphotoxin beta (LT-β) are pro-inflammatory TNF superfamily ligands that play important roles in immune system development (1, 2). The 25 kDa mature human LT-α is a secreted protein that shares 75% amino acid (aa) sequence identity with mouse and rat LT-α (3, 4). The 33 kDa mature human LT-β is a type II transmembrane protein that shares 73% aa sequence identity with mouse and rat LT-β within common regions of their extracellular domains (5). Relative to the human protein, mouse and rat LT-β have a 66 aa or 65 aa insertion within the ECD, respectively. LT-α can be secreted as a homotrimer that binds and activates TNF RI/TNFRSF1A, TNF RII/TNFRSF1B, HVEM/TNFRSF14, and Troy/TNFRSF19 (6-8). LT-α is required for development of the spleen, lymph nodes, and Peyer’s patches (9). It also regulates T cell homing to the gut and IgA induction (10). In addition, LT-α can form membrane-associated heterotrimers with two copies of LT-β on the surface of B, T, LTi, and ILC3 cells (2, 5, 11). The Lymphotoxin α1/β2 heterotrimer binds and activates the Lymphotoxin beta R/TNFRSF3 (LTβR) which is expressed on macrophages, dendritic cells, hepatocytes, intestinal epithelial cells (IEC), follicular dendritic cells (FDC), and high endothelial venules (HEV) (2, 12, 13). LTβR also serves as a receptor for LIGHT/TNFSF14 (14). LT-α1/β2 promotes the development of FDC networks and HEV in lymphoid tissue, the class switching of immature B cells for IgA production, and the production of homeostatic IL-22 by ILCs (10, 15-17). It can be shed by ADAM17 or MMP-8 mediated cleavage, and the released heterotrimer circulates in the serum and is elevated in synovial fluid of rheumatoid arthritis patients (18)