Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency
dc.contributor.author | Johnson, MB | |
dc.contributor.author | Ogishi, M | |
dc.contributor.author | Domingo-Vila, C | |
dc.contributor.author | De Franco, E | |
dc.contributor.author | Wakeling, MN | |
dc.contributor.author | Imane, Z | |
dc.contributor.author | Resnick, B | |
dc.contributor.author | Williams, E | |
dc.contributor.author | Galão, RP | |
dc.contributor.author | Caswell, R | |
dc.contributor.author | Russ-Silsby, J | |
dc.contributor.author | Seeleuthner, Y | |
dc.contributor.author | Rinchai, D | |
dc.contributor.author | Fagniez, I | |
dc.contributor.author | Benson, B | |
dc.contributor.author | Dufort, MJ | |
dc.contributor.author | Speake, C | |
dc.contributor.author | Smithmyer, ME | |
dc.contributor.author | Hudson, M | |
dc.contributor.author | Dobbs, R | |
dc.contributor.author | EXE-T1D consortium | |
dc.contributor.author | Quandt, Z | |
dc.contributor.author | Hattersley, AT | |
dc.contributor.author | Zhang, P | |
dc.contributor.author | Boisson-Dupuis, S | |
dc.contributor.author | Anderson, MS | |
dc.contributor.author | Casanova, J-L | |
dc.contributor.author | Tree, TI | |
dc.contributor.author | Oram, RA | |
dc.date.accessioned | 2024-07-04T13:25:43Z | |
dc.date.issued | 2024-04-18 | |
dc.date.updated | 2024-07-04T10:33:25Z | |
dc.description.abstract | We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients' primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation. | en_GB |
dc.identifier.citation | Vol. 221(6), article e20231704 | en_GB |
dc.identifier.doi | https://doi.org/10.1084/jem.20231704 | |
dc.identifier.uri | http://hdl.handle.net/10871/136584 | |
dc.identifier | ORCID: 0000-0002-6519-6687 (Johnson, Matthew B) | |
dc.identifier | ORCID: 0000-0002-1437-7891 (De Franco, Elisa) | |
dc.identifier | ORCID: 0000-0002-6542-9241 (Wakeling, Matthew N) | |
dc.identifier | ORCID: 0000-0001-5620-473X (Hattersley, Andrew T) | |
dc.identifier | ORCID: 0000-0003-3581-8980 (Oram, Richard A) | |
dc.language.iso | en | en_GB |
dc.publisher | Rockefeller University Press | en_GB |
dc.relation.url | https://doi.org/10.17632/4fwbcswj8d.1 | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/38634869 | en_GB |
dc.rights | © 2024 Johnson et al. Open access. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). | en_GB |
dc.title | Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2024-07-04T13:25:43Z | |
dc.identifier.issn | 0022-1007 | |
exeter.place-of-publication | United States | |
dc.description | This is the final version. Available on open access from Rockefeller University Press via the DOI in this record | en_GB |
dc.description | Data availability: Raw bulk RNASeq and scRNASeq datasets generated in this study are deposited in the SRA under BioProject accession no. PRJNA1084900. Preprocessed scRNASeq data and analysis scripts are deposited in the Mendeley Data repository (https://doi.org/10.17632/4fwbcswj8d.1). All other raw and processed data are available from the corresponding authors upon request. | en_GB |
dc.identifier.eissn | 1540-9538 | |
dc.identifier.journal | Journal of Experimental Medicine | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_GB |
dcterms.dateAccepted | 2024-03-13 | |
rioxxterms.version | VoR | en_GB |
rioxxterms.licenseref.startdate | 2024-04-18 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2024-07-04T13:23:24Z | |
refterms.versionFCD | VoR | |
refterms.dateFOA | 2024-07-04T13:25:54Z | |
refterms.panel | A | en_GB |
refterms.dateFirstOnline | 2024-04-18 |
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