Abstract
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.
Highlights
T cell-mediated adaptive immune response depends on precisely controlled lymphocyte trafficking [1, 2]
Using a mouse strain with T cell lineage-specific ablation of the β-subunit of GGTase-I, we demonstrate that protein geranylgeranylation controls T cell migration by regulating chemokine-receptorproximal signaling
Protein geranylgeranylation promotes the development of inflammatory Th17 cells while inhibiting naive T cells differentiation into Foxp3+ iTreg cells in vitro
Summary
T cell-mediated adaptive immune response depends on precisely controlled lymphocyte trafficking [1, 2]. In the presence of cognate antigen, antigen-specific T cells undergo activation, proliferation and differentiation into effector T cells that subsequently leave SLOs and travel through the circulation to peripheral target sites to orchestrate immune responses culminating in the elimination of pathogens or neoplastic cells [3] Likewise, such trafficking processes has been targeted to treat autoimmune diseases. The exquisite process of lymphocyte trafficking is critically regulated by three types of receptorsselectins, chemokine receptors and integrins [4].
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