Figure 1.

LIGHT signaling network. The arrows indicate the ligand–receptor interactions; single arrows indicate monodirectional; double-headed arrows indicate bidirectional signaling. LIGHT is a ligand for both HVEM and LTβR. DcR3 competitively inhibits LIGHT binding to LTβR and HVEM, blocking their signaling actions. LIGHT expression requires activation of T cells, whereas differentiated effector cells, such as neutrophils and NK cells, constitutively express LIGHT. HVEM also binds the two immunoglobulin superfamily members, BTLA and CD160. CD160 has two forms, as transmembrane and the dominant glycosphingolipid-linked form. In cells that coexpress HVEM, CD160, and BTLA, CD160 competes with BTLA for HVEM serving to downmodulate inhibitory BTLA signaling. As an example of bidirectional signaling, HVEM activates BTLA’s inhibitory pathway and reciprocally BTLA initiates HVEM’s activation of NF-κB transcription factors. Lymphocytes can coexpress HVEM, BTLA and CD160, forming complexes in cis. For example, naive T cells are initially restricted to BTLA and HVEM coexpression; however, following activation CD8 effector T cells coexpress all four proteins. The binding interactions among these proteins occur at intercellular contacts, such as T cell–dendritic cells during antigen recognition. Soluble LIGHT binds its receptors with high affinity, thus acting in a systemic fashion. In contrast, the relative low affinity of HVEM for BTLA and CD160 requires cell contact to activate signaling.