A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1

Abstract

T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I–like molecules. We describe a diverse population of human γδ T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a γδTCR–MR1–antigen complex starkly contrasts with all other TCR–MHC and TCR–MHC-I-like complex structures. Namely, the γδTCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 α3 domain. A similar pattern of reactivity was observed for diverse MR1-restricted γδTCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human γδ T cells and redefine the parameters for TCR recognition.

The Role of Gamma Delta T Cells in Autoimmune Rheumatic Diseases

“…These results indicate in vivo clonal expansion of Vδ1-and Vδ2-expressing γδ T cells in the PB of RA patients contrasting with a synovial T cell infiltrate which consists largely of polyclonally expanded γδ T cells, but showing clonal dominance in some patients [40]. Moreover, it appears that γδ T cells may expand in RA synovium to consist a unique population characteristically enriched in Vδ1 + T cells and often co-expressing Vγ8 and Vγ3 genes, which suggests they recognize MR1 [41]. In summary, the synovium in RA contains γδ T cells with a polyclonal repertoire, although sometimes containing oligoclonal expansions common to different joints.…”

“…Taken together, these reports support the idea that Vδ1 + γδ T cells in the synovium may be responding to local antigens expressed on synoviocytes, whereas the Vγ9Vδ2 T cells that enter the joint in response to inflammatory stimuli, participate locally by recognizing phosphoantigens presented by butyrophilins expressed in the synovium (Figure 1). [27,37,38,40,41,48]. Chemokines produced in inflamed synovium, attract C-X-C motif chemokine receptor (CXCR)5 and C-C motif chemokine receptor (CCR)3 expressing Vγ9 + T cells to the synovium [27].…”

Human γδ TCR Repertoires in Health and Disease

“…Only a few direct TCR ligands were identified to date. Those are either endogenous MHC-related (e.g., endothelial protein C receptor (EPCR), MR1 or CD1d) or MHC-unrelated proteins (e.g., annexin A2) [7][8][9][10]. 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].…”

Antigen recognition by human γδ T cells: one step closer to knowing

“…Ground‐breaking research by Rigau et al 3 and Karunakaran et al 4 now sheds neon lights on this phenomenon, identifying the key role of butyrophilin 2A1 (BTN2A1) in Vγ9/Vδ2 T‐cell phosphoantigen sensing (Figure 1). BTN2A1 is joining an illustrious family of only a handful of confirmed ligands for human γδ T cells that comprise diverse molecules such as endothelial protein C receptor, annexin A2 and, most recently, also the MHC‐related molecule MR1 2,6 …”

“…The clear implication of BTN2A1 in human Vγ9/Vδ2 T‐cell responses is a sort of homecoming for γδ T‐cell aficionados, because the related protein BTN3A1 had already been shown to be required for Vγ9/Vδ2 T‐cell responses to phosphoantigens 7 . Other butyrophilin family members with γδ T‐cell regulatory activity include BTNL3/BTNL8 (human Vγ4 + T cells), Btnl1/Btnl6 (mouse Vγ7 + T cells) and Skint1/Skint2 (mouse Vγ5 + T cells) 8 .…”