Structural basis of malaria RIFIN binding by LILRB1-containing antibodies

Yiwei Chen, Kai Xu, Luca Piccoli, Mathilde Foglierini, Joshua Tan, Wenjie Jin, Jason Gorman, Yaroslav Tsybovsky, Baoshan Zhang, Boubacar Traore, Chiara Silacci-Fregni, Claudia Daubenberger, Peter D. Crompton, Roger Geiger, Federica Sallusto, Peter D. Kwong and Antonio Lanzavecchia ()
Additional contact information
Yiwei Chen: Università della Svizzera italiana
Kai Xu: National Institutes of Health
Luca Piccoli: Università della Svizzera italiana
Mathilde Foglierini: Università della Svizzera italiana
Joshua Tan: Università della Svizzera italiana
Wenjie Jin: Università della Svizzera italiana
Jason Gorman: National Institutes of Health
Yaroslav Tsybovsky: Frederick National Laboratory for Cancer Research
Baoshan Zhang: National Institutes of Health
Boubacar Traore: University of Sciences, Techniques and Technologies of Bamako
Chiara Silacci-Fregni: Università della Svizzera italiana
Claudia Daubenberger: University of Basel
Peter D. Crompton: National Institutes of Health
Roger Geiger: Università della Svizzera italiana
Federica Sallusto: Università della Svizzera italiana
Peter D. Kwong: National Institutes of Health
Antonio Lanzavecchia: Università della Svizzera italiana

Nature, 2021, vol. 592, issue 7855, 639-643

Abstract: Abstract Some Plasmodium falciparum repetitive interspersed families of polypeptides (RIFINs)—variant surface antigens that are expressed on infected erythrocytes1—bind to the inhibitory receptor LAIR1, and insertion of DNA that encodes LAIR1 into immunoglobulin genes generates RIFIN-specific antibodies2,3. Here we address the general relevance of this finding by searching for antibodies that incorporate LILRB1, another inhibitory receptor that binds to β2 microglobulin and RIFINs through their apical domains4,5. By screening plasma from a cohort of donors from Mali, we identified individuals with LILRB1-containing antibodies. B cell clones isolated from three donors showed large DNA insertions in the switch region that encodes non-apical LILRB1 extracellular domain 3 and 4 (D3D4) or D3 alone in the variable–constant (VH–CH1) elbow. Through mass spectrometry and binding assays, we identified a large set of RIFINs that bind to LILRB1 D3. Crystal and cryo-electron microscopy structures of a RIFIN in complex with either LILRB1 D3D4 or a D3D4-containing antibody Fab revealed a mode of RIFIN–LILRB1 D3 interaction that is similar to that of RIFIN–LAIR1. The Fab showed an unconventional triangular architecture with the inserted LILRB1 domains opening up the VH–CH1 elbow without affecting VH–VL or CH1–CL pairing. Collectively, these findings show that RIFINs bind to LILRB1 through D3 and illustrate, with a naturally selected example, the general principle of creating novel antibodies by inserting receptor domains into the VH–CH1 elbow.

Date: 2021
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DOI: 10.1038/s41586-021-03378-6

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