HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes

Abstract

HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4 + T cell activation. In this study, we show that HDAC6 contributes to the cytotoxic function of CD8 + T cells. Immunization studies revealed defective cytotoxic activity in vivo in the absence of HDAC6. Adoptive transfer of wild-type or Hdac6

Sailing to and Docking at the Immune Synapse: Role of Tubulin Dynamics and Molecular Motors

“…HDAC6-silenced CD4 T cells showed a similar hyper-acetylation of tubulin than taxol-treated cells and even higher centrosome polarization than control cells ( 90 ). Likewise, in HDAC6-deficient CD8 T cells, the polarization of the centrosome is also higher than in control cells (it is closer to the IS) and tubulin acetylation is increased ( 91 ). Taxane (paclitaxel and docetaxel) binding to MTs was mapped to the β-tubulin subunit on the MT inner surface ( 92 ); the initially accepted model proposed that taxanes and other MT-stabilizing agents reach the binding pocket by diffusing through the MT wall.…”

“…In fact, the knockout mouse for Kif5b , the KHC involved, is embryonic lethal, showing perinuclear clustering of lysosomes and mitochondria. Kinesin-1 is helped in the transport of lytic granules to the IS by the action of HDAC6 ( 91 ). In HDAC6 knockout T cells, the acetylation of MTs is highly increased, but the centrosomal polarization to the IS of either silenced CD4 or knockout CD8 T cells was even enhanced ( 90 , 91 ).…”

“…Kinesin-1 is helped in the transport of lytic granules to the IS by the action of HDAC6 ( 91 ). In HDAC6 knockout T cells, the acetylation of MTs is highly increased, but the centrosomal polarization to the IS of either silenced CD4 or knockout CD8 T cells was even enhanced ( 90 , 91 ). Kinesin-1 ability to bind and move over MT is increased by acetylation at Lys40 of α-tubulin in the lumen of MTs ( 106 ).…”

“…Indeed, the use of cell-extracts of intact MT networks and single fluorescently labeled motor proteins to study motility through total internal reflection fluorescence microscopy (TIRFm) unveiled that acetylated MTs are predominantly bundled, which enhances the number of kinesin binding sites and run lengths of the motor ( 107 ). However, in the case of HDAC6 knockout CD8 T cells, the kinesin-1 interaction with p150 Glued was defective, correlating with a defect in the final delivery of lytic granules at the IS and their degranulation, even though acetylation of MTs was highly increased ( 91 ).…”

Cellular defence or viral assist: the dilemma of HDAC6

“…One possible explanation for HDAC6-enhanced T cell-mediated cytotoxicity is that CTLs are highly motile cells and require a dynamic cytoskeleton to actively approach potential target cells, whereas inhibition of HDAC6 is known to reduce cell migration. A recent study has demonstrated that HDAC6 is an effector of the immune cytotoxic response that acts by affecting the dynamics, transport and secretion of lytic granules by CTLs [116]. Taken together, the works summarized above demonstrate that HDAC6 is an essential component of autophagy-based immune response and an effector of the CTL response to viral infection.…”