BTLA is an immunoglobulin domain-containing glycoprotein expressed on T cells, resting B cells, macrophages, DCs and, to a lesser extent, NK cells. BTLA acts as an inhibitory receptor on T cells, as anti-BTLA treatment results in T cell proliferation, and BTLA knockout mice demonstrate hyper-responsive immune activation. Subsequently, herpesvirus entry mediator (HVEM), a tumor necrosis factor receptor, was identified as a natural ligand for BTLA in mice and humans. Expression of HVEM by antigen-presenting cells (APCs) was capable of inducing BTLA-dependent T cell inhibition.
BTLA belongs to the immunoglobulin superfamily, along with CTLA-4 and PD-1, which characteristically binds to B7 family members. HVEM is a member of the tumor necrosis factor receptor family, and the BTLA/HVEM interaction is the first to demonstrate crosstalk between these two receptor families. Prior to the discovery of the BTLA/HVEM interaction, HVEM was known to bind LIGHT and lymphotoxin-α, both tumor necrosis factor ligands. While the BTLA/HVEM interaction results in a co-inhibitory signal, the HVEM/LIGHT interaction results in a co-stimulatory signal through HVEM.
In melanoma patients, BTLA was demonstrated to be expressed on tumor-specific T cells both in circulation and in metastatic lymph nodes. HVEM was subsequently shown to be expressed in the majority of cultured melanoma cell lines and metastatic melanoma samples. The interaction of BTLA on tumor specific T cells and HVEM on melanoma cells resulted in T cell inhibition, which could be reversed by treatment with a BTLA blocking antibody. BTLA/HVEM interaction plays a key role in the regulation of inflammatory, autoimmune, and antitumor responses, and is an important target for cancer immunotherapy drug discovery. Therapeutically targeting BTLA and HVEM remains in pre-clinical stages as the bidirectional signaling pathways of BTLA/HVEM and HVEM/LIGHT are further elucidated.
