Alternative titles; symbols
HGNC Approved Gene Symbol: LTBR
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,375,160-6,391,566 (from NCBI)
Crowe et al. (1994) demonstrated that the tumor necrosis factor receptor-related protein is the human receptor for the heterotrimer of lymphotoxin-alpha (153440) and lymphotoxin-beta (600978). This LT-alpha/LT-beta heterotrimer is assumed to take part in immunologic reactions by cell-cell contact, but does not bind to either TNFR1 (191190) or TNFR2 (191191). Nakamura et al. (1995) isolated the LT-beta receptor cDNA from a cDNA library of murine embryonic heart mRNA, using the signal sequence trap (SST) method, a strategy for cloning secreted proteins and type I membrane proteins (Tashiro et al., 1993). This method, which does not require specific functional assays, takes advantage of the fact that their precursors carry amino-terminal signal sequences. The deduced amino acid sequence of the mouse LT-beta receptor is 66% identical to that of the human protein. Northern blot analysis of various organs in adult mice showed that expression levels of LTBR mRNA were strong in lung, liver, and kidney, moderate in heart and testes, but weak in brain, thymus, spleen, and lymph nodes. Nakamura et al. (1995) speculated that, since the mouse receptor was already expressed in 7-day post coitus embryos, the LT-alpha/LT-beta receptor system may have some function in early embryogenesis.
Silva-Santos et al. (2005) reported that double-positive T cells regulate the differentiation of early thymocyte progenitors and gamma-delta cells by a mechanism dependent on the transcription factor ROR-gamma-t (602943) and the lymphotoxin-beta receptor. Silva-Santos et al. (2005) suggested that the finding provokes a revised view of the thymus, in which lymphoid tissue induction-type processes coordinate the developmental and functional integration of the 2 T cell lineages.
Lo et al. (2007) identified lymphotoxin (see 153440) and LIGHT (TNFSF14; 604520), tumor necrosis factor cytokine family members that are primarily expressed on lymphocytes, as critical regulators of key enzymes that control lipid metabolism. Dysregulation of LIGHT expression on T cells resulted in hypertriglyceridemia and hypercholesterolemia. In low density lipoprotein receptor (606945)-deficient mice, which lack the ability to control lipid levels in the blood, inhibition of lymphotoxin and LIGHT signaling with a soluble LTBR decoy protein attenuated the dyslipidemia. Lo et al. (2007) concluded that the immune system directly influences lipid metabolism and that lymphotoxin modulating agents may represent a novel therapeutic route for the treatment of dyslipidemia.
By linkage analysis with recombinant inbred mouse strains, Nakamura et al. (1995) demonstrated that the Tnfcr locus is close to the Tnfr1 gene on mouse chromosome 6. Presumably, the human homolog is located on 12p13.
By histologic examination, Chin et al. (2003) observed considerable perivascular infiltration of activated T lymphocytes in tissues from Lta -/- and Ltbr -/- mice relative to age-matched wildtype mice, particularly in lung, pancreas, liver, and kidney. This pattern was similar to that observed in Aire (607358) -/- mice. Real-time PCR and immunofluorescence analysis showed that the thymi of Lta -/-, Ltb -/-, and Ltbr -/- mice had markedly reduced Aire and insulin expression in thymic medullary epithelial cells. ELISA analysis demonstrated increased anti-DNA antibody and anti-IgG rheumatoid factor in 5- to 7-month-old Lta -/- and Ltbr -/- mice. Chin et al. (2003) noted that LTBR signaling is mediated by the RELB (604758)-p52 (NFKB2; 164012)-NFKB (164011) pathway and that thymi from Relb -/- mice totally lack Aire expression. Thus, they suggested that RELB may represent a point of convergence of signals that regulate AIRE.
To investigate T-cell involvement in IgA nephropathy (161950), Wang et al. (2004) examined a murine model that spontaneously develops T cell-mediated intestinal inflammation accompanied by pathologic features similar to those of human IgA nephropathy. Intestinal inflammation mediated by member 14 of the tumor necrosis factor ligand superfamily (TNFSF14; 604520), which is a ligand for Ltbr, not only stimulated IgA overproduction in the gut but also resulted in defective IgA transportation into the gut lumen, causing a dramatic increase in serum polymeric IgA. Wang et al. (2004) found that engagement of Ltbr by Tnfsf14 was essential for both intestinal inflammation and hyperserum IgA syndrome in this model.
Heikenwalder et al. (2008) generated symmetrical soft-tissue granulomas in mice with and without Prnp (176640) and found that, following intraperitoneal inoculation of prions, they could only detect prion in Prnp +/+ granuloma and spleen homogenates. Immunohistochemical analysis demonstrated expression of Mfge8 (602281), a marker of follicular dendritic cells (FDCs), in spleen but not in granulomas, indicating that, in addition to FDCs, stromal Ltbr-positive mesenchymal cells can express prions. Heikenwalder et al. (2008) concluded that granulomas can act as clinically silent reservoirs of prion infectivity and that lymphotoxin-dependent prion replication can occur in inflammatory stromal cells that are distinct from FDCs.
Chin, R. K., Lo, J. C., Kim, O., Blink, S. E., Christiansen, P. A., Peterson, P., Wang, Y., Ware, C., Fu, Y.-X. Lymphotoxin pathway directs thymic Aire expression. Nature Immun. 4: 1121-1127, 2003. [PubMed: 14517552] [Full Text: https://doi.org/10.1038/ni982]
Crowe, P. D., VanArsdale, T. L., Walter, B. N., Ware, C. F., Hession, C., Ehrenfels, B., Browning, J. L., Din, W. S., Goodwin, R. G, Smith, C. A. A lymphotoxin-beta-specific receptor. Science 264: 707-710, 1994. [PubMed: 8171323] [Full Text: https://doi.org/10.1126/science.8171323]
Heikenwalder, M., Kurrer, M. O., Margalith, I., Kranich, J., Zeller, N., Haybaeck, J., Polymenidou, M., Matter, M., Bremer, J., Jackson, W. S., Lindquist, S., Sigurdson, C. J., Aguzzi, A. Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas. Immunity 29: 998-1008, 2008. [PubMed: 19100703] [Full Text: https://doi.org/10.1016/j.immuni.2008.10.014]
Lo, J. C., Wang, Y., Tumanov, A. V., Bamji, M., Yao, Z., Reardon, C. A., Getz, G. S., Fu, Y.-X. Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science 316: 285-288, 2007. [PubMed: 17431181] [Full Text: https://doi.org/10.1126/science.1137221]
Nakamura, T., Tashiro, K., Nazarea, M., Nakano, T., Sasayama, S., Honjo, T. The murine lymphotoxin-beta receptor cDNA: isolation by the signal sequence trap and chromosomal mapping. Genomics 30: 312-319, 1995. [PubMed: 8586432] [Full Text: https://doi.org/10.1006/geno.1995.9872]
Silva-Santos, B., Pennington, D. J., Hayday, A. C. Lymphotoxin-mediated regulation of gamma-delta cell differentiation by alpha-beta T cell progenitors. Science 307: 925-928, 2005. [PubMed: 15591166] [Full Text: https://doi.org/10.1126/science.1103978]
Tashiro, K., Tada, H., Heilker, R., Shirozu, M., Nakano, T., Honjo, T. Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins. Science 261: 600-603, 1993. [PubMed: 8342023] [Full Text: https://doi.org/10.1126/science.8342023]
Wang, J., Anders, R. A., Wu, Q., Peng, D., Cho, J. H., Sun, Y., Karaliukas, R., Kang, H.-S., Turner, J. R., Fu, Y.-X. Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy. J. Clin. Invest. 113: 826-835, 2004. [PubMed: 15067315] [Full Text: https://doi.org/10.1172/JCI20096]