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Publication Detail
Regulation of CTLA-4 recycling by LRBA and Rab11.
  • Publication Type:
    Journal article
  • Publication Sub Type:
  • Authors:
    Janman D, Hinze C, Kennedy A, Halliday N, Waters E, Williams C, Rowshanravan B, Hou TZ, Minogue S, Qureshi OS, Sansom DM
  • Publication date:
  • Journal:
  • Status:
    Published online
  • Country:
  • Language:
  • Keywords:
    CTLA-4, LRBA, Rab GTPase, Rab11, T cells, recycling, trafficking
CTLA-4 is an essential regulator of T cell immune responses whose intracellular trafficking is a hallmark of its expression. Defects in CTLA-4 trafficking due to LRBA deficiency cause profound autoimmunity in humans. CTLA-4 rapidly internalises via a clathrin-dependent pathway followed by poorly characterised recycling and degradation fates. Here we explore the impact of manipulating Rab GTPases and LRBA on CTLA-4 expression to determine how these proteins affect CTLA-4 trafficking. We observe that CTLA-4 is distributed across several compartments marked by Rab5, Rab7 and Rab11 in both Hela and Jurkat cells. Dominant negative (DN) inhibition of Rab5 resulted in increased surface CTLA-4 expression and reduced internalisation and degradation. We also observed that constitutively active (CA) Rab11 increased, whereas DN Rab11 decreased, CTLA-4 surface expression via an impact on CTLA-4 recycling, indicating CTLA-4 shares similarities with other recycling receptors such as EGFR. Additionally, we studied the impact of manipulating both LRBA and Rab11 CTLA-4 trafficking. In Jurkat cells LRBA deficiency was associated with markedly impaired CTLA-4 recycling and increased degradation that could not be corrected by expressing CA Rab11. Moreover LRBA deficiency reduced CTLA-4 co-localisation with Rab11 suggesting that LRBA is upstream of Rab11. These results show that LRBA is required for effective CTLA-4 recycling by delivering CTLA-4 to Rab11 recycling compartments and in its absence CTLA-4 fails to recycle and undergoes degradation.
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Inst for Liver and Digestive Hlth
Div of Infection & Immunity
Div of Infection & Immunity
Education (Div of Med)
Div of Infection & Immunity
Div of Infection & Immunity
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