BTNL2 As an Immunomodulatory Ligand: Delineating an Orphan Immune Checkpoint

Butyrophilin-like 2 (BTNL2) is a Type I transmembrane glycoprotein of the immunoglobulin superfamily (IgSF) that functions as a tissue-specific immune checkpoint regulator with structural homology to B7 ligands. BTNL2 suppresses T cell activation by attenuating IL-2 secretion through the AP-1, NFAT, and NF-κB pathways. Functional and in vivo studies have established BTNL2 as a regulator of immune responses and have implicated it in tumor immune evasion and cancer progression. Therapeutically, BTNL2 modulation offers dual opportunities: agonists to restore tolerance in autoimmunity and transplantation, and antagonists to overcome tumor immune evasion. Structurally, BTNL2 differs from other canonical checkpoint ligands of the IgSF superfamily, as it contains two sets of IgV and IgC domains connected by a heptameric linker sequence. However, even after two decades of research, its cognate receptor remains unidentified.