Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

Abstract

SignificanceAlthough gamma delta (γδ) T cells compose an evolutionarily conserved third lineage of diversified lymphocytes, alongside αβ T cells and B cells, they can seem overtly different across species and tissues. Thus, human blood γδ cells show butyrophilin (BTN)3A1-dependent responses to metabolites (“phosphoantigens”) not seen by rodent γδ cells, whereas some rodent, γδ-rich compartments, notably in the skin, lack obvious human counterparts. Recently, however, mouse and human intraepithelial gut γδ cells were found to be regulated by pairings of BTN-like genes. This study now shows that BTN3A1 also functions as a pairing, with its subcellular trafficking and optimal activity both regulated by BTN3A2. Hence, seemingly diverse γδ cell biologies across species and tissues are underpinned by conserved mechanisms.

A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation

“…An interesting feature of the ''complete'' BTN3A1 structure is that there is a ''juxtamembrane'' region (a coiled-coil a-helical structure [JM] domain), and similar domains have been shown to be vital in signal transduction in other systems (Deng and Li, 2015). The JM region locates to the N terminus of the B30.2 domain and connects to the transmembrane domain of the BTN3A1 molecule and the essentiality of the JM domain of BTN3A1 in Vg9Vd2 T cell activation has been reported by several groups (Hsiao et al, 2014;Peigné et al, 2017;Rhodes et al, 2015;Vantourout et al, 2018). Thus, we next asked how HMBPP binding (including the H351 b / a conformational change) might be conveyed to the JM domain and lead to the extracellular signaling event.…”

TCR repertoire analysis reveals phosphoantigen-induced polyclonal proliferation of Vγ9Vδ2 T cells in neonates and adults

“…The current model of pAg presentation by BTN3A1 is evidenced by direct binding of pAgs to the intracellular region of BTN3A1 17,22,23 . Heteromerization of BTN3A1 with other family members occurs and other molecules seem to be involved 22,24‐26 . After activation, adult Vγ9Vδ2 T cells rapidly proliferate, release cytokines and are able to mediate cell killing 27‐29 .…”

Human γδ TCR Repertoires in Health and Disease

“…virus-infected or transformed cells) and are potent antigens leading to the rapid anti-bacterial, anti-viral or anti-cancer responses of Vγ9Vδ2 + T cells [12,13,54]. These small molecules interact with an intracellular domain of BTN3A1 (B30.2) and are thought to induce conformational changes that lead to Vγ9Vδ2 + T cell activation [15,17,50].…”

“…In particular, EPCR and annexin A2, as well as phosphorylated metabolites of isoprenoid synthesis, were described as serving as self-antigens that indicate cellular stress [5,[11][12][13]. Most importantly, B7 receptor family-like butyrophilin (BTN) and butyrophilin-like (BTNL) molecules have been implied in the development of specific epithelial and circulating γδ T cell subsets [14][15][16][17] and as direct γδ TCRs ligands [18][19][20][21]. Advances in next-generation sequencing (NGS) analysis of human γδ TCR repertoires, together with the recent identification of γδ TCR ligands, shed light on the vast TCR diversity of human γδ T cells, thereby pointing to a complex role in health and disease.…”