1. Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.
- Author
-
Casanova, Jean-Laurent, Tree, Timothy, Oram, Richard, Johnson, Matthew, Ogishi, Masato, Domingo-Vila, Clara, De Franco, Elisa, Wakeling, Matthew, Imane, Zineb, Resnick, Brittany, Williams, Evangelia, Galão, Rui, Caswell, Richard, Russ-Silsby, James, Seeleuthner, Yoann, Rinchai, Darawan, Fagniez, Iris, Benson, Basilin, Dufort, Matthew, Speake, Cate, Smithmyer, Megan, Hudson, Michelle, Dobbs, Rebecca, Hattersley, Andrew, Zhang, Peng, Boisson-Dupuis, Stephanie, Anderson, Mark, and Quandt, Zoe
- Subjects
Infant ,Newborn ,Humans ,Child ,Preschool ,Child ,B7-H1 Antigen ,Diabetes Mellitus ,Type 1 ,Programmed Cell Death 1 Receptor ,Autoimmunity ,Homozygote - 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.
- Published
- 2024