p97-mediated proteostasis is a checkpoint for late-stage thymocyte positive selection.

p97-mediated proteostasis is essential for late-stage thymocyte positive selection, with its loss causing a severe block in CD8+ lineage development in mice.

• Why it matters: Understanding the mechanisms behind thymocyte development is crucial for insights into immune system function and potential immunodeficiencies. The role of p97 in this process was previously undefined, representing a significant knowledge gap.
• What they did: Researchers used genetic deletion and pharmacological inhibition of p97 in mice, revealing a stage- and lineage-specific requirement, especially affecting double-positive thymocytes and CD8+ lineage commitment.
• The result: Loss of p97 causes intrathymic arrest of immature DP cells, peripheral T-cell lymphopenia, accumulation of ubiquitinated proteins, and disrupted IL-7R/JAK signaling, with JAK activation partially rescuing thymocyte development.