RIPK1 inhibition restricts DNT cell pathogenesis and ameliorates autoimmune lymphoproliferative syndrome

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.