Recombinant Human Lymphotoxin beta R (LTbR) Fc Chimera, CF

Lymphotoxin beta receptor (LT betaR), previously called TNF RIII or TNF R‑related protein (TNF Rrp), is a type I transmembrane glycoprotein within the TNF receptor superfamily, designated TNFRSF3 (1‑3). Human LT betaR cDNA encodes 435 amino acids (aa) including a 30 aa signal peptide, a 197 aa extracellular domain (ECD), a 21 aa transmembrane domain, and a 187 aa cytoplasmic domain. The ECD contains four cysteine‑rich motifs characteristic of the TNF receptor superfamily (1, 2). Within the ECD, human LT betaR shares 67‑74% aa sequence identity with mouse, rat, canine, porcine, equine and bovine LT betaR. Soluble LT betaR can be formed by proteolytic cleavage of the ECD, and is an inhibitor of transmembrane LT betaR, as is recombinant LT betaR, which inhibits autoimmunity (3‑6). Potential human isoforms include a 416 aa form with an alternate N‑terminal signal sequence, and a 328 aa form that begins at aa 108 (7). LT betaR is expressed by visceral, lymphoid, and other stroma, epithelia and myeloid cells, but not lymphocytes (2, 4). LT betaR ligands include homotrimers of LIGHT (TNFSF14; also a ligand for HVEM) and the heterotrimeric lymphotoxin LT alpha1/ beta2 (3, 4, 6). Depending on the cell type and expression of TRAF3, activation of LT betaR has been shown to induce canonical (IKK/RelA; pro‑inflammatory) or alternative (NIK/RelB; lymphoid organogenic) NF kappaB activation (6, 8). LT betaR is expressed on mesenchymal stromal organizing cells that give rise to stroma of primary (thymus), secondary (tonsils, lymph nodes and Peyers patches) and tertiary (ectopic inflammatory) lymphoid structures (3‑5, 9‑11). Secondary immune tissues are absent in LT betaR‑deficient mice (3 ‑ 5). LT betaR engagement induces production of IL‑7, RANK, TRANCE/RANK L, VEGF‑C, adhesion molecules such as VCAM‑1, ICAM‑1 and MAdCAM, and chemokines such as CXCL13, CCL19 and CCL21 (3, 9 ‑ 11). LT betaR is expressed by hepatocytes, is up‑regulated in regeneration, hepatitis and hepatocellular carcinoma, and influences lipid metabolism and atherosclerosis (4, 6, 12). It regulates cell growth and can initiate inflammation‑related carcinogenesis (6, 12).