The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation

Abstract

The tumor necrosis factor (TNF) receptor superfamily member herpesvirus entry mediator (HVEM) (TNFRSF14) regulates T-cell immune responses by activating both inflammatory and inhibitory signaling pathways. HVEM acts as both a receptor for the canonical TNF-related ligands, LIGHT [lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed on T lymphocytes] and lymphotoxin-α, and as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules. The ability of HVEM to interact with multiple ligands in distinct configurations creates a functionally diverse set of intrinsic and bidirectional signaling pathways that control both inflammatory and inhibitory responses. The HVEM system is integrated into the larger LTβR and TNFR network through extensive shared ligand and receptor usage. Experimental mouse models and human diseases indicate that dysregulation of HVEM network may contribute to autoimmune pathogenesis, making it an attractive target for drug intervention.

Fig. 1. Ligand-receptor specificity in the HVEM network

The arrows connecting the TNF related and the Ig ligands (upper panel) to their cognate receptors (lower panel) define the ligand-receptor specificity in the HVEM network. Ligation of HVEM by any of its ligands in trans leads to NFκB activation. The immunotyrosine inhibitory motif (ITIM) in BTLA recruits tyrosine phosphatases (SHP1/2) limiting antigen receptor signals. Herpes simplex virus envelope glycoprotein D (gD) engages HVEM as an entry route and expressed in the infected cell. UL144 is encoded by human cytomegalovirus and binds BTLA. LTα and decoy receptor-3 are soluble, and CD160 is shown in its GPI linkage to the membrane.

Fig. 2. Molecular model of the activating and inhibitory pathways of HVEM

(A) Membrane LIGHT displaces BTLA from binding with HVEM due to membrane restriction. (B) Cooperative binding between soluble LIGHT, LTα with HVEM and BTLA. A trimolecular complex of LIGHT/LTα–HVEM–BTLA is composed of three molecules of soluble LIGHT/LTα, HVEM and BTLA. (C) Formation of HVEM-BTLA/CD160/gD cis-complexes. Cis-interaction between HVEM, BTLA, CD160 and HSV gD inhibits HVEM binding to its ligands in trans.

Fig. 3. HVEM Interactions regulating T-cell immune responses

(A). Engagement of HVEM by membrane LIGHT during T-T cell interactions leads to the activation of the NFκB-RelA, AP-1, and Akt pathways that enhances cell proliferation, cytokine production, and survival of HVEM-expressing cells. Similarly, engagement of HVEM by BTLA in trans induces NF-κB activation and promotes T-cell survival. Alternative interactions of HVEM with BTLA, e.g. in cis configuration, also promotes T-cell survival by a mechanism that has not been fully elucidated. (B). Engagement of BTLA on T cells by HVEM expressed in antigen-presenting cells (APCs) induces ITIM phosphorylation on BTLA facilitating the recruitment of phosphatases SHP-1 and SHP-2, which once activated, downregulates the TCR signaling pathway resulting in reduced cellular activation, proliferation, and cytokine production. Similarly, HVEM binding to CD160 expressed in T cells leads to reduced phosphorylation of the CD3ζ chain and intracellular proteins what result in decreased T-cell activation and proliferation. The mechanism by which CD160 engagement by HVEM attenuates T-cell responses remains unknown. In naive T cells, the HVEM and BTLA cis configuration negatively regulates NF-κB signaling pathway that may sustain the naive phenotype by blocking ligands in the surrounding microenvironment.