DNA sequence is located on chromosome 20. Transcription consists of 7 exons and 6 introns, spanning 3.6kb.
A shorter transcription variance (M68E) has been identified, and is transcribed from 3 exons and 2 introns spanning 1.9kb as illustrated above. The difference occurs at the 5 untranslated region, but the two transcripts encode the same isoform. Mice do not have a gene orthologue to human TNFRSF6B.
TNFRSF68B mRNA in Northen blot presents as a 1.2-knt band.

TNFRSF6B protein is 300-amino acid long, and has a molecular weight of 35 kD. Although TNFRSF6B belongs to the TNFR superfamily, it lacks the transmembrane and cytosolic domains in its sequence, and is a secreted protein. It contains 4 TNFR cystein-rich regions, as illustrated above.
TNFRSF6B can be easily cleaved between Arg²¹⁸ and Ala²¹⁹ in biological fluids and solutions. It has thus a very short (about 20 min) half-life in serum and in vivo. Mutation of arginine residue at position 218 to glutamine makes TNFRSF6B resistant to proteolysis, and significantly prolongs its half-life.
TNFRSF6B can bind to the TNF family members FasL, LIGHT and TL1A. It does not bind to other known TNF family members. Human TNFRSF6B can bind to mouse FasL, LIGHT and TL1A. This allows human DcR3/TNFRSF6B to function in mouse models both in vitro and in vivo.
The role of TNFRSF6B in apoptosis is obvious. FasL is a well-known molecule involved in apoptosis. LIGHT is a ligand for HVEM and LTbetaR, in addition to being a ligand for TNFRSF6B. LIGHT can induce apoptosis in cells expressing both HVEM and LTbetaR, or LTbetaR alone. TL1A, a member of the TNF family, can evoke apoptosis via its receptor, DR3. Consequently, the interaction of TNFRSF6B with FasL, LIGHT, and TL1A blocks apoptosis mediated by Fas, HVEM, LTbetaR and DR3.

Normal tissue and cells express low-level TNFRSF6B, and healthy individuals have near-background serum TNFRSF6B levels. About 60% of malignant tumors of various tissue origins overexpress TNFRSF6B, and these patients have elevated serum TNFRSF6B levels. Serum TNFRSF6B levels of tumor patients are positively correlated to the degree of tumor malignancy and status of metastasis. It is hypothesized that malignant tumor cells secrete TNFRSF6B as a way to achieve survival advantage by blocking multiple apoptosis pathways.
Hepatocytes in liver cirrhosis have augmented TNFRSF6B expression and patients with liver cirrhosis have increased serum TNFRSF6B levels.
TNFRSF6B expression is low in resting T cells but is augmented in activated T cells, which probably represents a fine-tuning mechanism to balance the need for clonal expansion and subsequent massive activation-induced T cell death. About 40% of systemic lupus erythematosus patients have elevated serum TNFRSF6B levels.
TNFRSF6B expression in rheumatoid arthritis fibroblast-like synoviocytes is increased by TNFalpha

TNFRSF6B is a secreted protein, and is thus detected in body fluids. However, it can also be detected in cytoplasm before it is secreted.

As TNFRSF6B can block ligands from interacting with Fas, HVEM, LTbetaR, and DR3, all of which mediate apoptosis, it is thus can effectively inhibit apoptosis in many cell types. It is believed that many types of malignant tumors gain survival advantage by secreting TNFRSF6B which blocks tumor cell apoptosis.
Syngeneic islets transplanted to diabetes recipients survive better in the presence of administered exogenous human TNFRSF6B, due to the blockage of FasL-, LIGHT- and TL1A-triggered islets apoptosis. Transgenic expression of human TNFRSF6B in NOD mouse islets reduces diabetes pathogenesis, again, due to anti-apoptotic effect of TNFRSF6B.
The forward signaling from FasL to Fas, and from LIGHT to HVEM can provide costimulation signals to resting T cells. Blocking of these two signaling pathways reduces T cell responses to antigens. As LIGHT and FasL, although being ligands, are also transmembrane proteins, and are capable of reversely transducing costimulating signals into T cells, TNFRSF6B can also block such reverse signaling. The end result is that TNFRSF6B can reduce several costimulation pathways in T cells and inhibit T cell immune responses, such as cytokine secretion and proliferation in vitro, and cardiac allograft rejection in vivo in mouse models.
When human TNFRSF6B is linked to a transmembrane domain and is expressed on the mouse tumor cell surface, it can effectively trigger T cell costimulation via LIGHT and FasL reverse signaling, and cause effective tumor vaccination in mouse models.
When human TNFRSF6B is transgenically expressed in mice, it causes a systemic lupus erythrematosus-like syndrome. The expression of TNFRSF6B in bone marrow-derived cells is sufficient to induce this phenotype.
Recombinant human TNFRSF6B ameliorates an autoimmune crescentic glomerulonephritis model in mice.
TNFRSF6B can influence dendritic cells which in turn drive T cells to differentiate into Th2 cells.
TNFRSF6B can inhibit actin polymerization of T cells upon mitogen stimulation, and repress T-cell pseudopodium formation, which is known to be important for cell-cell interaction. As a consequence, T-cell aggregation after activation is suppressed by either soluble or solid phase TNFRSF6B.
Human T cells pretreated with soluble or solid-phase TNFRSF6B are compromised in migration in vitro and in vivo toward CXCL12. Mechanistically, a small GTPase Cdc42 fails to be activated after TNFRSF6B pretreatment of human T cells, and further downstream, p38 mitogen-activated protein kinase activation, actin polymerization, and pseudopodium formation are all down-regulated in the treated T cells.
Phagocytic activity toward immune complexes and apoptotic bodies as well as the production of free radicals and proinflammatory cytokines in response to lipopolysaccharide are impaired in TNFRSF6B-treated macrophages.

Not reported yet.