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<p>The thymus is a primary lymphoid organ in which diverse and self-tolerant T cells are produced from bone marrow-derived hematopoietic progenitors. Progressive, age-associated thymic involution reduces T-cell output and impairs adaptive immunity; however, the molecular mechanisms underlying this process remain elusive. Here, we report that the conditional deletion of the RNA-binding proteins Zfp36l1 and Zfp36l2 in thymic epithelial cells (TECs) leads to a pronounced reduction in the number of TECs during the embryonic stage and early neonatal stage, despite a largely preserved thymus size. Postnatally, these mice exhibit excessive medullary TEC (mTEC) expansion, elevated intrathymic proinflammatory cytokine production, FOXN1 downregulation, and premature thymic involution. These findings reveal a protective role for Zfp36 Tristetraprolin (TTP) family proteins in regulating cytokine levels within the thymic microenvironment and preventing premature thymic involution. Moreover, our results suggest a previously unappreciated connection between central tolerance induction and the onset of age-associated thymic involution.</p>

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RNA-binding proteins Zfp36l1 and Zfp36l2 protect against premature thymic involution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月16日

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  • Jianxun Han,
  • Mahdieh Golzari-Sorkheh,
  • Vinothkumar Rajan,
  • Juan Carlos Zúñiga-Pflücker

摘要

The thymus is a primary lymphoid organ in which diverse and self-tolerant T cells are produced from bone marrow-derived hematopoietic progenitors. Progressive, age-associated thymic involution reduces T-cell output and impairs adaptive immunity; however, the molecular mechanisms underlying this process remain elusive. Here, we report that the conditional deletion of the RNA-binding proteins Zfp36l1 and Zfp36l2 in thymic epithelial cells (TECs) leads to a pronounced reduction in the number of TECs during the embryonic stage and early neonatal stage, despite a largely preserved thymus size. Postnatally, these mice exhibit excessive medullary TEC (mTEC) expansion, elevated intrathymic proinflammatory cytokine production, FOXN1 downregulation, and premature thymic involution. These findings reveal a protective role for Zfp36 Tristetraprolin (TTP) family proteins in regulating cytokine levels within the thymic microenvironment and preventing premature thymic involution. Moreover, our results suggest a previously unappreciated connection between central tolerance induction and the onset of age-associated thymic involution.