Frontiers in Immunology (Mar 2021)

A Requirement of Protein Geranylgeranylation for Chemokine Receptor Signaling and Th17 Cell Function in an Animal Model of Multiple Sclerosis

  • Gregory Swan,
  • Gregory Swan,
  • Jia Geng,
  • Eunchong Park,
  • Quanquan Ding,
  • John Zhou,
  • Ciana Walcott,
  • Junyi J. Zhang,
  • Hsin-I Huang,
  • Gianna Elena Hammer,
  • Donghai Wang,
  • Donghai Wang

DOI
https://doi.org/10.3389/fimmu.2021.641188
Journal volume & issue
Vol. 12

Abstract

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Precisely controlled lymphocyte migration is critically required for immune surveillance and successful immune responses. Lymphocyte migration is strictly regulated by chemokines and chemokine receptors. Here we show that protein geranylgeranylation, a form of post-translational protein lipid modification, is required for chemokine receptor-proximal signaling. Mature thymocytes deficient for protein geranylgeranylation are impaired for thymus egress. Circulating mature T cells lacking protein geranylgeranylation fail to home to secondary lymphoid organs or to transmigrate in response to chemokines in vitro. Mechanistically, protein geranylgeranylation modifies the γ-subunits of the heterotrimeric small GTPases that are essential for chemokine receptor signaling. In addition, protein geranylgeranylation also promotes the differentiation of IL-17-producing T helper cells while inhibiting the differentiation of Foxp3+ regulatory T cells. Finally, mice with T cell lineage-specific deficiency of protein geranylgeranylation are resistant to experimental autoimmune encephalomyelitis induction. This study elucidated a critical role of protein geranylgeranylation in regulating T lymphocyte migration and function.

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