A Novel PD-L1 Splice Isoform Modulates β Cell Communication in Response to Interferon Signaling

A novel splice isoform of PD-L1, called PD-L1Δ3, has been discovered in human beta cells and islets. This isoform arises from an alternative splicing process, triggered by interferon (IFN) signaling or viral infections. Unlike the full-length PD-L1 protein, PD-L1Δ3 is not found on the cell surface but remains intracellular. This intracellular localization prevents PD-L1Δ3 from interacting with PD-1, a receptor that helps regulate immune cell activity.

The research team found that PD-L1Δ3 is present in higher amounts in islets from individuals with single autoantibody positivity (AAB+) and those diagnosed with type 1 diabetes (T1D). Unlike the protein encoded by the full-length PD-L1 gene, PD-L1Δ3 does not bind to PD-1, thereby losing its ability to suppress the activity of CD8+ and CD4+ T cells.

These T cells play a crucial role in the immune response against the beta cells in T1D patients. Additionally, PD-L1Δ3 is not efficiently incorporated into extracellular vesicles (EVs), which are small particles released by cells that can carry various biomolecules, including proteins.

Interestingly, the researchers also identified a specific genetic variant in the splicing site of the PD-L1 gene. This germline variant, found in siblings with neonatal T1D, leads to the production of PD-L1Δ3. This variant shares the same intracellular retention, reduced PD-1 binding, and impaired EV PD-L1 expression as PD-L1Δ3.

The findings suggest that PD-L1Δ3 is an IFN-induced splice variant that diverts PD-L1 from its immunoregulatory, EV-competent form. This discovery highlights a post-transcriptional mechanism that influences beta cell immune communication, potentially contributing to the development and progression of T1D.