Structural insight into T cell coinhibition by PD-1H (VISTA)

Slater, Benjamin T.; Han, Xue; Chen, Lieping; Xiong, Yong

doi:10.1073/pnas.1908711117

Title: Structural insight into T cell coinhibition by PD-1H (VISTA)

Journal Article · Thu Jan 09 00:00:00 EST 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1908711117· OSTI ID:1582072

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Programmed death-1 homolog (PD-1H), a CD28/B7 family molecule, coinhibits T cell activation and is an attractive immunotherapeutic target for cancer and inflammatory diseases. The molecular basis of its function, however, is unknown. Bioinformatic analyses indicated that PD-1H has a very long Ig variable region (IgV)-like domain and extraordinarily high histidine content, suggesting that unique structural features may contribute to coinhibitory mechanisms. In this paper we present the 1.9-Å crystal structure of the human PD-1H extracellular domain. It reveals an elongated CC′ loop and a striking concentration of histidine residues, located in the complementarity-determining region-like proximal half of the molecule. We show that surface-exposed histidine clusters are essential for robust inhibition of T cell activation. PD-1H exhibits a noncanonical IgV-like topology including an extra “H” β-strand and “clamping” disulfide, absent in known IgV-like structures, that likely restricts its orientation on the cell surface differently from other IgV-like domains. These results provide important insight into a molecular basis of T cell coinhibition by PD-1H.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); Boehringer Ingelheim; National Institutes of Health (NIH); United Technologies Corporation Endowed Chair; National Institute of General Medical Sciences (NIGMS)

Grant/Contract Number:: AC02-06CH11357; S10OD021527

OSTI ID:: 1582072

Alternate ID(s):: OSTI ID: 1599419

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Vol. 117 Journal Issue: 3; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 27 works

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59 BASIC BIOLOGICAL SCIENCES
PD-1H
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structure
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cancer immunotherapy

Title: Structural insight into T cell coinhibition by PD-1H (VISTA)

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