BTN2A Immune Checkpoint Molecule for Drug Development

Immune Checkpoint BTN2A

Butyrophilin 2A (BTN2A) molecules are identified as transmembrane proteins of the butyrophilins (BTN)/butyrophilin-like (BTNL) superfamily, among which there are 8 members (BTN1A1, BTN2A1/2A2, BTN3A1/3A2/3A3, BTNL2 and MOG) are reported to be located in the major histocompatibility complex (MHC) class I region of human chromosome 6 (Ch6).

Structure of BTN2A

BTN/BTNL molecules share significant sequence homology with the B7 family, composed of a juxtamembrane (JTM) domain, a single-pass TM domain, immunoglobulin (Ig)C-IgV extracellular domains, and, an intracellular B30.2 domain in most members including BTN2A.

Fig.1 Protein domain structure of BTN/BTNL molecules and model of BTN2A1-IgV.¹

Expression of BTN2A

BTN2A1 and BTN2A2 were detected in many tissues. In mice, BTN2A2 protein was found expressed on the surface of nonactivated CD19⁺ B cells, CD11c⁺ dendritic cells (DC), NK1.1⁺ NK cells, CD11b⁺F4/80⁺ peritoneal macrophages and on CD3⁺ T cells.

Functions of BTN2A

Multiple members of the BTN/BTNL family have been found to be in the impairment of T cell responses. Besides, genetic polymorphisms in BTN molecules are associated with multiple inflammations in humans, preventing excessive immune responses in autoimmune and inflammatory diseases. It has been reported that changes in high-mannose oligosaccharide modification and increased expression levels of BTN2A1 in tumors, can influence the binding of the lectin-like receptor DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN). BTN2A2 was reported as a negative costimulatory molecule that modulates T cell responses by inhibiting T helper type (Th) cell development by binding to anti-CD3-stimulated T cells, inhibiting Zap70, CD3ϵ, and Erk1/2 phosphorylation, related to specific signaling events of the prosurvival PI3K and Akt pathways. It was also demonstrated that BTN2A2 significantly modulates ILC2 in inflammations, regulating the cross-talk between T ceIn studies during recent years, BTN2A was discovered to play an indispensable role in BTN3A-mediated Vg9Vd2 T cell cytotoxicity against cancer cells. BTN2A1 binds to the T cell receptor directly by germline-encoded regions on the Vγ9 cell surface and interacts directly with BTN3A1, instead of depending on P-Ag stimulation.

Fig. 2 BTN2A in BTN3A-mediated Vg9Vd2 T cell cytotoxicity.³

BTN2A Immune Checkpoint Molecule for Drug Development

BTN2A molecules are potential therapeutic targets for regulating immune responses in autoimmune and inflammatory diseases and BTN3A-mediated Vg9Vd2 T cell cytotoxicity in sensing of phosphoantigens accumulated in malignant cells. Currently, studies on BTNA2 molecules are still mainly focused on basic research. However, it is very inspiring to explore and clarify more independent or synergistic mechanisms of functions of BTN2A for the development of drugs and therapeutic methods.

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References

Rhodes, et al. "Regulation of immunity by butyrophilins." Annual review of immunology 34 (2016): 151-172.
Karunakaran, Mohindar M., et al. "Butyrophilin-2A1 directly binds germline-encoded regions of the Vγ9Vδ2 TCR and is essential for phosphoantigen sensing." Immunity 52.3 (2020): 487-498.
Cano, Carla E., et al. "BTN2A1, an immune checkpoint targeting Vγ9Vδ2 T cell cytotoxicity against malignant cells." Cell Reports 36.2 (2021).

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