Herpesvirus entry mediator–B- and T-lymphocyte attenuator protein–protein interaction (HVEM–BTLA interaction)

The HVEM–BTLA protein–protein interaction is a unique immune checkpoint involving the herpesvirus entry mediator (HVEM, TNFRSF14) and the B- and T-lymphocyte attenuator (BTLA, CD272). This interaction is notable for bridging the tumor necrosis factor receptor (TNFR) and immunoglobulin (Ig) superfamilies, facilitating bidirectional signaling that regulates the activation, proliferation, and survival of T and B cells (1.1.1, 1.1.2). Under physiological conditions, the interaction helps maintain immune homeostasis and prevents autoimmunity by recruiting phosphatases like SHP-1 and SHP-2 to attenuate antigen receptor signaling (1.2.3, 1.3.2). However, in the context of cancer, tumors often exploit this pathway to evade immune surveillance, with high expression of HVEM or BTLA correlating with poor prognosis in diseases such as melanoma and lung cancer (1.3.3, 2.4.1). Therapeutic strategies targeting this axis include antagonistic antibodies, such as tifcemalimab, which block the inhibitory signal to enhance anti-tumor immunity, and agonistic antibodies designed to treat autoimmune and inflammatory diseases by suppressing overactive immune cells (2.3.1, 2.5.2). The complexity of the HVEM network, which includes other ligands like LIGHT and CD160, presents both opportunities for multi-modal therapy and challenges in achieving target specificity without unintended immune consequences (1.3.1, 2.4.3).

Other names

HVEM/BTLA axisBTLA-HVEM complexTNFRSF14-CD272 interactionHVEM-BTLA signaling pathwayHVEM-BTLA bidirectional checkpoint

Antagonistic blockade of the HVEM-BTLA interaction to relieve immune suppression in oncology, or agonistic activation of BTLA to suppress overactive immune responses in autoimmune and inflammatory conditions.