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RIPK1 inhibition restricts DNT cell pathogenesis and ameliorates autoimmune lymphoproliferative syndrome

ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is an immune disorder characterized by pathological lymphoproliferation, multi-lineage autoimmunity, and lymphoma predisposition. A hallmark of ALPS is the expansion of double-negative T (DNT) cells, which correlates with disease severity, yet the mechanisms underlying their aberrant generation and pathogenicity remain elusive. Using single-cell transcriptomics in pediatric ALPS patients, we identified a pathogenic effector DNT subset (GZMhiCXCR5hi) exhibiting high expression of cytotoxic and co-stimulatory genes. Through the development of a novel apoptosis-defective Caspase8-/-Ripk3D143N/D143N murine model that recapitulates early-onset ALPS. We demonstrate that RIPK1 kinase activity and RIPK3 scaffolding function drive ALPS pathogenesis, through directing CXCL13-CXCR5-mediated tissue infiltration of pathogenic DNT cells and enabling their peripheral reprogramming from CD8⁺ T cells through CREMα-mediated CD8 silencing. Strikingly, both ALPS patient-derived and murine ALPS-derived CD8⁺ T cells showed marked susceptibility to activation-induced conversion to the pathogenic DNT cells, a process effectively blocked by RIPK1 inhibition. Remarkably, pharmacological inhibition of RIPK1 kinase significantly reduced DNT generation, abolished their tissue infiltration, and alleviated autoimmune pathology in murine ALPS models. Our findings establish RIPK1 as a critical driver of DNT-mediated pathogenesis and identify RIPK1 inhibition as a promising therapeutic strategy for ALPS and potentially other DNT-associated autoimmune disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299218 | GEO | 2026/09/10

REPOSITORIES: GEO

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RIPK1 inhibition restricts DNT cell pathogenesis and ameliorates autoimmune lymphoproliferative syndrome

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