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

Area of Science:

• Immunology
• Genetics
• Endocrinology

Background:

• Inherited PD-1 deficiency can lead to fatal autoimmune diseases, including type 1 diabetes (T1D).
• The role of PD-L1, the ligand for PD-1, in preventing early-onset T1D and its impact on leukocyte development is less understood.

Purpose of the Study:

• To investigate the consequences of a specific CD274 gene variant causing loss-of-function PD-L1 in siblings with neonatal-onset T1D.
• To compare the immunological and hematological profiles of PD-L1 deficient individuals with those of PD-1 deficient individuals.

Main Methods:

• Genetic analysis of siblings with neonatal-onset T1D.
• Overexpression experiments to confirm loss-of-function PD-L1 variant.
• Cytometric immunophenotyping and single-cell RNA sequencing of blood leukocytes.

Main Results:

• Two siblings with neonatal-onset T1D were identified with a splice-site variant in CD274, leading to a non-functional PD-L1 protein.
• Leukocyte development and transcriptional profiles were largely normal in PD-L1 deficient siblings.
• This contrasts with extensive dysregulation observed in PD-1 deficient individuals.

Conclusions:

• PD-1 and PD-L1 are essential for preventing early-onset T1D.
• PD-L1 deficiency does not result in fatal autoimmunity or widespread leukocyte dysregulation, unlike PD-1 deficiency.