Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More

Abstract

Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention.

Keywords: BTN2A1; BTN3A1; T cell receptor; butyrophilin; immune therapy; phosphoantigen; tumor; γδ T cell.

Figure 1

Butyrophilins as members of the B7 family. Left: A comparison of structures of extracellular domains of programmed death ligand 1 (PD-L1: yellow) and Butyrophilin 3A1 (BTN3A1: blue). Shown is an overlay of the tertiary structure of both proteins. Differences of the C-domains of both molecules result mainly from a twist in the orientation of V- and C-Ig domains. In an exclusive overlay of V domain alone, similarities in the Ig-V domains would be even more pronounced. Picture is modified from (3). Right: Schematic representation of human BTN/BTNL family members and mouse Skint1. The protein domains are exemplified for BTN3A1. ERMAP (Erythroblast membrane-associated protein), MOG (Myelin-Oligodendrocyte glycoprotein). Skint 1 (Selection and upkeep of intraepithelial T-cells 1). The indicated Stop codon inactivates the Skint1 function in the DETC deficient FVB/N-Tac mouse strain (4).

Figure 2

Working hypothesis on PAg-recognition by Vγ9Vδ2 T cells. Left: Under physiological conditions, BTN2A1 binds to the hypervariable region 4 (CDR4 or HV4) of the Vγ9 region of the Vγ9Vδ2TCR. This controls thymic development and homeostasis of Vγ9Vδ2 T cells. Right: Infection or cell transformation increases PAg-levels in the presenting or tumor cell. This leads to PAg-binding to the B30.2 domain of BTN3A1, and subsequent binding of the B30.2-PAg complex to the intracellular domain of BTN2A1. The resulting complex might include additional proteins, which finally bind all CDRs regions of γ and δ chain and trigger Vγ9Vδ2 T cell activation. Please note that so far neither direct binding of the TCR to BTN3A nor existence of an additional ligand recruited by the PAg-binding BTN3A has been demonstrated.