Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency

EXE-T1D Consortium, Matthew B. Johnson, Masato Ogishi, Clara Domingo-Vila, Elisa De Franco, Matthew N. Wakeling, Zineb Imane, Brittany Resnick, Evangelia Williams, Rui Pedro Galão, Richard Caswell, James Russ-Silsby, Yoann Seeleuthner, Darawan Rinchai, Iris Fagniez, Basilin Benson, Matthew J. Dufort, Cate Speake, Megan E. Smithmyer, Michelle HudsonRebecca Dobbs, Zoe Quandt, Andrew T. Hattersley, Peng Zhang, Stephanie Boisson-Dupuis, Mark S. Anderson, Jean Laurent Casanova, Timothy I. Tree, Richard A. Oram

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalThe Journal of experimental medicine
Issue number6
Publication statusPublished - 3 Jun 2024


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