biostudies-literatureJohnson MBNCATS NIH HHSNIDDK NIH HHSNCRR NIH HHSNIAID NIH HHSDiabetes UKWellcome TrustNIH HHSe20231704https://www.ebi.ac.uk/biostudies/studies/S-EPMC11032109biostudies-literatureUnknown221(6)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-deficThe Journal of experimental medicineHuman inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.PMC11032109R01 AI095983K12 DK133995UL1TR001866U19 AI142737UL1 TR001866098395/Z/12/Z16/0005529U19 AI162568Ogishi MQuandt ZTree TIWilliams EHagopian WBenson BSpeake CSeeleuthner YRoep BOWakeling MNCaswell RZhang PFagniez IJohnson MBAnderson MSOram RADomingo-Vila CResnick BRuss-Silsby JRinchai DSmithmyer MEDe Franco ECasanova JLBoisson-Dupuis SHudson MWeedon MNEXE-T1D consortiumHattersley ATDufort MJGalao RPDobbs RImane ZfalseHuman inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency.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-defic2024-01-01T00:00:00Z2024 Jun2026-05-29T11:26:19.158Z2026-04-08T04:28:27.6ZS-EPMC110321093863486910.1084/jem.20231704