Dominant-negative PSMB10 disrupts immunoproteasome assembly and leads to transient T lymphopenia

Immunoproteasomes are specialized multiprotein proteases that degrade intracellular proteins. Their products serve as peptides for human leukocyte antigen class I presentation playing a key role in antiviral defense and self-tolerance. Monoallelic variants in immunoproteasome genes including proteasome subunit β 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. Despite this, hematopoietic stem cells differentiated into T cells ex vivo, and the patient developed normal naïve T cell counts and a diverse T cell antigen receptor repertoire within the first year of life in contrast to all previously reported patients.