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

β cell expression of the immune checkpoint ligand PD-L1 (encoded by CD274) limits autoimmune β cell destruction in type 1 diabetes (T1D). β cell display PD-L1 not only at the cell surface but also secreted on extracellular vesicles (EVs), which bind PD-1 and restrain CD8+ T cell activation. β cell IFN signaling is an early driver of T1D pathogenesis, yet the mechanisms linking IFN signaling to the fate of PD-L1 protein remain undefined. Here, we identify an IFN- and coxsackievirus-inducible alternatively spliced isoform of PD-L1, PD-L1Δ3, lacking cassette exon 3 and generated in human β cells and islets in response to IFN signaling or viral infection. PD-L1Δ3 transcripts are elevated in islets from donors with single autoantibody positivity (AAB+) and T1D. Unlike full-length PD-L1, which localizes to the plasma membrane, PD-L1Δ3 is retained intracellularly and loses the capacity to bind PD-1. Functionally, PD-L1Δ3 fails to suppress CD8+ and CD4+ T cell proliferation, activation, and cytotoxic cytokine release, and is not efficiently sorted into EVs. Convergently, a germline CD274 splice-site variant (c.682+1G>A) found in siblings with neonatal T1D yields a protein with the same intracellular retention, reduced β cell PD-1 binding, and reduced β cell and circulating EV PD-L1. Together these findings define PD-L1Δ3 as an IFN-induced splice variant that diverts PD-L1 away from its immunoregulatory, EV-competent form, revealing a post-transcriptional axis that shapes β cell immune communication.