B and T lymphocyte attenuator (BTLA) is a protein that regulates the body’s immune system. It functions as an immune checkpoint molecule, helping maintain immune balance. This prevents the immune system from becoming overactive, which is important for overall health.
BTLA’s Molecular Identity
BTLA is a protein found on the surface of various immune cells, including T cells, B cells, natural killer (NK) cells, and dendritic cells. It is a type I glycosylated transmembrane protein. The human BTLA gene encodes a protein composed of 289 amino acids.
A specific binding partner for BTLA is the Herpesvirus Entry Mediator (HVEM), also known as TNFRSF14. HVEM is broadly present on both immune and non-immune cells. The interaction between BTLA and HVEM is a one-to-one complex, where BTLA binds to the N-terminal cysteine-rich domain of HVEM.
Regulation of Immune Responses
BTLA functions to modulate immune responses primarily through an inhibitory role, particularly on T cells. This inhibitory action helps prevent excessive immune activation, acting like a braking mechanism. When BTLA binds to HVEM, it initiates a cascade of signals inside the immune cell.
This interaction leads to the recruitment of SH2 domain-containing tyrosine phosphatases, such as SHP-1 and SHP-2. These phosphatases remove phosphate groups from signaling molecules involved in T cell activation. This dephosphorylation dampens signals downstream of the T cell receptor, inhibiting T cell activation, proliferation, and the production of pro-inflammatory signaling molecules.
The cytoplasmic domain of BTLA contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM), both involved in recruiting SHP-1 and SHP-2. This mechanism reduces the overall immune response. While BTLA’s primary role is inhibitory, it also has a growth factor receptor-bound protein-2 (Grb-2) recognition motif in its cytoplasmic domain, which can activate the PI3K signaling pathway.
BTLA in Health and Disease
In a healthy body, BTLA contributes to maintaining immune homeostasis. By downregulating excessive immune responses, BTLA helps prevent autoimmune reactions and modulates inflammation, limiting chronic inflammation that can lead to tissue damage. However, dysregulation of BTLA can contribute to disease states.
In cancer, tumor cells can exploit BTLA signaling to evade the immune system. High levels of BTLA expression have been observed in several types of cancer, including melanoma, non-small cell lung cancer, hepatocellular carcinoma, and colorectal cancer. This allows cancer cells to grow and spread unchecked by suppressing anti-tumor immunity.
In autoimmune diseases, BTLA helps prevent the immune system from attacking healthy tissues and limits chronic inflammation, a feature of conditions like rheumatoid arthritis and inflammatory bowel disease. Research also indicates BTLA’s involvement in infectious diseases and transplantation rejection.
Therapeutic Potential
Understanding BTLA’s role provides avenues for therapeutic interventions, particularly in cancer treatment. By blocking the interaction between BTLA and HVEM, therapies aim to release the “brakes” on the immune system, enhancing the immune response against cancer cells.
Anti-BTLA antibodies are being investigated to restore T cell activity and boost anti-tumor responses. These therapies prevent BTLA from transmitting inhibitory signals, invigorating exhausted T cells and improving their ability to proliferate and produce effector molecules like IFN-γ and TNF-α. This approach aims to enhance the efficacy of existing immunotherapies and offer new options for patients with difficult-to-treat cancers.
In autoimmune disorders, activating BTLA could suppress exaggerated immune responses. Agonistic BTLA modulators, which mimic HVEM and activate BTLA’s inhibitory function, could help restore immune balance in conditions like rheumatoid arthritis, lupus, and multiple sclerosis. This dual potential highlights BTLA as a versatile target for modulating immune responses across various diseases.