Dataset Information

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(-/-)CD8(+)T cells to Rag1(-/-)mice demonstrated specific impairment in CD8(+)T cell responses against vaccinia infection. Mechanistically, HDAC6-deficient cytotoxic T lymphocytes (CTLs) showed defective in vitro cytolytic activity related to altered dynamics of lytic granules, inhibited kinesin-1-dynactin-mediated terminal transport of lytic granules to the immune synapse and deficient exocytosis, but not to target cell recognition, T cell receptor (TCR) activation or interferon (IFN)? production. Our results establish HDAC6 as an effector of the immune cytotoxic response that acts by affecting the dynamics, transport and secretion of lytic granules by CTLs.

SUBMITTER: Nunez-Andrade N

PROVIDER: S-EPMC5023047 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.

Núñez-Andrade Norman N Iborra Salvador S Trullo Antonio A Moreno-Gonzalo Olga O Calvo Enrique E Catalán Elena E Menasche Gaël G Sancho David D Vázquez Jesús J Yao Tso-Pang TP Martín-Cófreces Noa Beatriz NB Sánchez-Madrid Francisco F

Journal of cell science 20160211 7

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(-/-)CD8(+)T cells to Rag1(-/-)mice demonstrated specific impairment ...[more]

PMID: 26869226

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Project description:Cytotoxic T lymphocytes (CTLs) are important in controlling some viral infections, and therapies involving the transfer of large numbers of cancer-specific CTLs have been successfully used to treat several types of cancers in humans. While the molecular mechanisms of how CTLs kill their targets are relatively well understood, we still lack a solid quantitative understanding of the kinetics and efficiency by which CTLs kill their targets in vivo. Collagen-fibrin-gel-based assays provide a tissue-like environment for the migration of CTLs, making them an attractive system to study T cell cytotoxicity in in vivo-like conditions. Budhu.et al. systematically varied the number of peptide (SIINFEKL)-pulsed B16 melanoma cells and SIINFEKL-specific CTLs (OT-1) and measured the remaining targets at different times after target and CTL co-inoculation into collagen-fibrin gels. The authors proposed that their data were consistent with a simple model in which tumors grow exponentially and are killed by CTLs at a per capita rate proportional to the CTL density in the gel. By fitting several alternative mathematical models to these data, we found that this simple "exponential-growth-mass-action-killing" model did not precisely describe the data. However, determining the best-fit model proved difficult because the best-performing model was dependent on the specific dataset chosen for the analysis. When considering all data that include biologically realistic CTL concentrations (E≤107cell/mL), the model in which tumors grow exponentially and CTLs suppress tumor's growth non-lytically and kill tumors according to the mass-action law (SiGMA model) fit the data with the best quality. A novel power analysis suggested that longer experiments (∼3-4 days) with four measurements of B16 tumor cell concentrations for a range of CTL concentrations would best allow discriminating between alternative models. Taken together, our results suggested that the interactions between tumors and CTLs in collagen-fibrin gels are more complex than a simple exponential-growth-mass-action killing model and provide support for the hypothesis that CTLs' impact on tumors may go beyond direct cytotoxicity.

Dataset Information

HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.

Publications

HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes.

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