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The PD-1/PD-L1 Complex Resembles the Antigen-Binding Fv Domains of Antibodies and T Cell Receptors
David Yin-wei Lin, Yoshimasa Tanaka, Masashi Iwasaki, Apostolos G. Gittis, Hua-Poo Su, Bunzo Mikami, Taku Okazaki, Tasuku Honjo, Nagahiro Minato and David N. Garboczi
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 8 (Feb. 26, 2008), pp. 3011-3016
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25461175
Page Count: 6
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Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives "exhausted" virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response.
Proceedings of the National Academy of Sciences of the United States of America © 2008 National Academy of Sciences