Regulation of T cell response by a new member of the TNF receptor family, DcR3/TR6

TR6, also called DcR3, M68, is a soluble receptor of the TNFR superfamily. It has three identified ligands: FasL, LIGHT and TL1A, all TNF ligand superfamily members. TR6 can interfere with the interaction between FasL versus Fas, LIGHT versus HveA, and TL1 versus DR3. TR6 is over-expressed in some tumours. It has been proposed that TR6-secreting tumours use this molecule to evade immune surveillance and gain survival advantage.; In this project, the function of TR6 in immune regulation was investigated. As we have proven that human TR6 can cross-react with mouse LIGHT, and anti-human LIGHT mAb can bind to mouse LIGHT on the mouse T-cell surface, we use human TR6 and anti-human LIGHT monoclonal antibody to study the function of TR6 in the mouse system.; In the in vitro T cell response study, we have found that TR6 on solid phase can costimulate mouse T cell response in terms of proliferation, cytokine production and CTL activity. Blocking experiments indicate that soluble human LIGHT can block TR6-costimulated CTL activity. Anti-LIGHT mAb on solid phase also enhances T-cell proliferation. These effects indicate that LIGHT reverse signaling involves in the solid phase TR6 costimulated T cell response. Based on our findings in LIGHT signaling transduction, it is likely that, during T-cell activation, LIGHT forms capping and quickly moves into clustered TCR. The congregated LIGHT inside the TCR cluster interacts with other signaling molecules through its association with Grb2 to activate downstream signaling molecules such as ERK1/2 to costimulate T cell activation.; Further, we have explored the TR6 costimulatory function in tumour immunotherapy. As T cells express two TR6 ligands, i.e. FasL and LIGHT, both of which can reversely transduce positive costimulatory signals into T cells, we have developed a tumour vaccine based on surface TR6 expression on tumour cells. In vitro studies have shown that TR6 surface expression on tumour cells is able to costimulate both human and syngeneic mouse T-cell proliferation and cytokine production. In vivo studies have shown that TR6 surface expression reduces P815 mouse mastocytoma cell tumourigenicity, and induces specific anti-P815 tumour cell immunity. Vaccination with surface TR6 expressing tumour cells is effective in treating existing highly immunogenic as well as lowly immunogenic tumours; the therapeutic effects are enhanced when the vaccine is used in combination with Bacillus of Calmette and Guerin (BCG). These results indicate that expressing TR6 on tumour cell surface might be a very useful strategy in tumour immunotherapy. (Abstract shortened by UMI.)...