Herpesvirus entry mediator (HVEM) attenuates signals mediated by the lymphotoxin β receptor (LTβR) in human cells stimulated by the shared ligand LIGHT

- LIGHT signaling through its two receptors depends on their differential expression.
- LTβR mediates pro-inflammatory and pro-apoptotic signals when engaged by LIGHT.
- HVEM attenuates pro-apoptotic signals when both receptors are present.

Signals mediated by members of the tumor necrosis factor receptor superfamily modulate a network of diverse processes including initiation of inflammatory responses and altering cell fate between pathways favoring survival and death. Although such pathways have been well-described for the TNF-α receptor, less is known about signaling induced by the TNF superfamily member LIGHT and how it is differentially altered by expression of its two receptors LTβR and HVEM in the same cell. We used cell lines with different relative expression of HVEM and LTβR to show that LIGHT-induced signals mediated by these receptors were associated with altered TRAF2 stability and RelA nuclear translocation. Production of the inflammatory chemokine CXCL10 was primarily mediated by LTβR. Higher expression of HVEM was associated with cell survival, while unopposed LTβR signaling favored pathways leading to apoptosis. Importantly, restoring HVEM expression in cells with low endogenous expression recapitulated the phenotype of cells with higher endogenous expression. Together, our data provide evidence that relative expression of HVEM and LTβR modulates canonical NF-κB and pro-apoptotic signals stimulated by LIGHT.