Reciprocal expression of the TNF family receptor herpes virus entry mediator and its ligand LIGHT on activated T cells: LIGHT down-regulates its own receptor

The TNF receptor (TNFR) family plays a central role in the development of t he immune response, Here we describe the reciprocal regulation of the recen tly identified TNFR superfamily member herpes virus entry mediator (HVEM) ( TR2) and its ligand LIGHT (TL4) on T cells following activation and the mec hanism of this process. T cell activation resulted in down-regulation of HV EM and up-regulation of LIGHT, which were both more pronounced in CD8(+) th an CD4(+) T lymphocytes, The analysis of HVEM and LIGHT mRNA showed an incr ease in the steady state level of both mRNAs following stimulation. LIGHT, which was present in cytoplasm of resting T cells, was induced both in cyto plasm and at the cell surface. For HVEM, activation resulted in cellular re distribution, with its disappearance from cell surface. HVEM down-regulatio n did not rely on de novo protein synthesis, in contrast to the partial dep endence of LIGHT induction. Matrix metalloproteinase inhibitors did not mod ify HVEM expression, but did enhance LIGHT accumulation at the cell surface . However, HVEM down-regulation was partially blocked by a neutralizing mAb to LIGHT or an HVEM-Fc fusion protein during activation, As a model, we pr opose that following stimulation, membrane or secreted LIGHT binds to HVEM and induces receptor down-regulation. Degradation or release of LIGHT by ma trix metalloproteinases then contributes to the return to baseline levels f or both LIGHT and HVEM, These results reveal a self-regulating ligand/recep tor system that contributes to T cell activation through the interaction of T cells with each other and probably with other cells of the immune system .