E3 Ligase Rbx1 Orchestrates Thymus Development and Fate Determination of αβ-γδ T Cells

TL;DR

This study shows that the E3 ligase Rbx1 is crucial for thymus development and the fate of αβ-γδ T cells in mice.

Contribution

The study identifies Rbx1 as a key regulator of thymus development and γδ T cell fate determination.

Findings

Rbx1 loss causes thymus shrinkage and delayed T cell development.

Rbx1 deficiency increases immature γδ T cells and alters γδ T1/T17 populations.

Rbx1 loss affects Akt, NF-κB, and metabolic pathways in T cell progenitors.

Abstract

T lymphocytes consist of αβ and γδ T cells, which mature and differentiate from the same progenitor cells in the thymus. Cullin-RING ligases (CRLs), the largest family of ubiquitin ligases, require neddylation on the scaffold protein Cullins for their ligase activity. The role of neddylation–CRL system in thymus development and fate determination of αβ/γδ T cells remains elusive. Here, we generated conditional knockout mouse models with thymus individual deletion of Ube2m or Ube2f, 2 neddylation E2-conjugating enzymes, and Rbx1 or Sag, 2 dual neddylation and ubiquitylation E3 ligases. We found that only Rbx1, but not Ube2m/Ube2f, nor Sag, plays an essential role in thymus development and fate determination of αβ/γδ T cells. Specifically, Rbx1 loss causes shrinkage of the thymus, delayed T cell development, increased γδ T cells in the thymus, increased the ratio of immature Gzma+ γδ T cells, and decreased the ratio of the proliferative subpopulation. Some of these phenotypes were moderately rescued by simultaneous Bim deletion. Mechanistically, Rbx1 loss alters the Akt, NF-κB, and metabolic pathways in progenitor γδ T cells/DN3a cells. Finally, Rbx1 loss altered the γδ T1/T17 cell population in the thymus, suggesting that Rbx1 controls the fate of γδ T cells.

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