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Their products serve as peptides for human leukocyte antigen class I presentation playing a key role in antiviral defense and self-tolerance.<\/jats:p>\n                  <jats:p>Monoallelic variants in immunoproteasome genes including proteasome subunit \u03b2 type 10 have recently been associated with autoinflammatory diseases and severe combined immune deficiency. Their pathophysiological consequences remain poorly understood, and treatment options are scarce. We identified a newborn with severe T lymphopenia and a de novo dominant-negative PSMB10 p.G209R mutation after pathological T cell receptor excision circle newborn screening. We further applied molecular modeling, proteomics, transcriptomics, and ex vivo T lymphopoiesis. Simulations predicted, and biochemical studies confirmed, impaired immunoproteasome assembly and function leading to defective viral sensing and antigen presentation signatures in interferon-treated fibroblasts. 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