4.6 Article

PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells

Journal

JOURNAL OF IMMUNOLOGY
Volume 202, Issue 3, Pages 966-978

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1801288

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Funding

  1. Canadian Institutes of Health Research [FDN-148400]

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T cell development depends on sequential interactions of thymocytes with cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells. PSMB11 is a catalytic proteasomal subunit present exclusively in cTECs. Because proteasomes regulate transcriptional activity, we asked whether PSMB11 might affect gene expression in cTECs. We report that PSMB11 regulates the expression of 850 cTEC genes that modulate lymphostromal interactions primarily via the WNT signaling pathway. cTECs from Psmb11(-/-) mice 1) acquire features of medullary thymic epithelial cells and 2) retain CD8 thymocytes in the thymic cortex, thereby impairing phase 2 of positive selection, 3) perturbing CD8 T cell development, and 4) causing dramatic oxidative stress leading to apoptosis of CD8 thymocytes. Deletion of Psmb11 also causes major oxidative stress in CD4 thymocytes. However, CD4 thymocytes do not undergo apoptosis because, unlike CD8 thymocytes, they upregulate expression of chaperones and inhibitors of apoptosis. We conclude that PSMB11 has pervasive effects on both CD4 and CD8 thymocytes via regulation of gene expression in cTECs.

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