Our data suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8+ T cells. The Selleck GW-572016 TNF receptor superfamily (TNFRSF) constitutes a group of structurally related cell surface glycoproteins that regulate innate and adaptive immunity 1. A subgroup of the TNFRSF

contains a conserved region within the cytoplasmic domain known as the death domain 1. Triggering of death domain-containing members of the TNFRSF can lead to the induction of apoptosis via activation of caspase-8 or stimulation of the MAP kinase and NF-κB signaling pathways. TNFRSF25, also known as death receptor 3, is most similar in sequence to TNFR1; however, unlike the widely distributed TNFR1, TNFRSF25 is expressed primarily on T cells 2, 3. The ligand for TNFRSF25 is TL1A, a TNF-like protein that exists either as a membrane-anchored protein or a soluble cytokine 4. TL1A is produced by activated DCs, monocytes, endothelial cells and T cells 4–6. TL1A costimulates T-cell production of effector cytokines in vitro 4, 6–8 and enhances the accumulation of CD4+ effector

T cells within the inflamed tissues Everolimus concentration in autoimmune and inflammatory disease models 6. TL1A also promotes Treg proliferation and attenuates Treg-mediated suppression of non-regulatory CD4+ T cells 9. In addition, TL1A has been shown to costimulate invariant NKT cells 10 and may have a role in enhancing NK cell-mediated tumor cell killing 11. In Megestrol Acetate contrast with the well-established costimulatory effects of TNFRSF25 on CD4+ T cells, little is known about its role in regulating CD8+ T-cell responses. Here we addressed the function of TNFRSF25 during CD8+ T-cell activation and in the setting of anti-tumor immunity in which CD8+ T cells play a critical role. Three transfected

J558L tumor cell lines that express relatively high levels of TL1A (Fig. 1A) were combined immediately before inoculation into mice. In T- and B-cell-deficient SCID mice TL1A-expressing J558L tumor cells grew with similar kinetics to control J558L cells transfected with the empty vector (Fig. 1B). In sharp contrast, TL1A-expressing J558L cells, but not control tumor cells, were rejected in immune competent BALB/c mice, demonstrating that tumor rejection requires an adaptive immune response (Fig. 1C). In many cases, TL1A-expressing J558L tumors grew initially following s.c. injection into BALB/c mice, but these tumors regressed and the majority of animals had no detectable tumors 70 days after initial tumor inoculation (Fig. 1C). Mice that rejected the TL1A-expressing J558L tumors were immune to a subsequent challenge with non-transfected J558L tumor cells (Fig. 1D and Supporting Information Fig. 1A). To assess the role of T-cell subsets in TL1A-mediated tumor rejection, we administered anti-CD4 or anti-CD8 depleting mAbs prior to inoculation with TL1A-expressing J558L tumor cells.