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Cytotoxic T lymphocyte effector function is independent of nucleus-centrosome dissociation.

ABSTRACT: Cytotoxic T lymphocytes (CTLs) kill tumorigenic and virally infected cells by targeted secretion of lytic granule contents. The precise point at which secretion occurs is directed by the centrosome docking at the immunological synapse (IS). The centrosome is highly dynamic in CTLs, lagging behind the nucleus in the uropod of migrating CTLs, but translocating across the entire length of the cell to dock at the IS when a target cell is recognized. While in most cell types, the centrosome is always closely associated with the nuclear membrane, in CTLs, it often appears to be dissociated from the nucleus, both in migrating cells and when forming an IS. We asked whether this dissociation is required for CTL killing, by expressing GFP-BICD2-NT-nesprin-3, which tethers the centrosome to the nucleus irreversibly. Immunofluorescence microscopy revealed that the centrosome polarized successfully to the central supramolecular activation complex (cSMAC) of the synapse in GFP-BICD2-NT-nesprin-3-expressing CTLs, with the centrosome and nucleus migrating together to the IS. CTLs in which the centrosome was "glued" to the nucleus were able to dock and release granules at the IS as effectively as mock-treated cells. These data demonstrate that CTL cytotoxicity is independent of centrosomal dissociation from the nuclear envelope.

SUBMITTER: Lui-Roberts WW

PROVIDER: S-EPMC3470926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS. Forty-eight patients from two independent cohorts fulfilling the Canada 2003 criteria for ME/CFS were evaluated with respect to cytotoxic lymphocyte phenotype and function. Results were compared to values from matched healthy controls. Reproducible differences between patients and controls were not found in cytotoxic lymphocyte numbers, cytotoxic granule content, activation status, exocytotic capacity, target cell killing, or cytokine production. One patient expressed low levels of perforin, explained by homozygosity for the PRF1 p.A91V variant. However, overall, this variant was present in a heterozygous state at the expected population frequency among ME/CFS patients. No single patient displayed any pathological patterns of cellular responses. Increased expansions of adaptive NK cells or deviant cytotoxic lymphocyte adrenaline-mediated inhibition were not observed. In addition, supervised dimensionality reduction analyses of the full, multidimensional datasets did not reveal any reproducible patient/control discriminators. In summary, employing sensitive assays and analyses for quantification of cytotoxic lymphocyte differentiation and function, cytotoxicity lymphocyte aberrances were not found among ME/CFS patients. These assessments of cytotoxic lymphocytes therefore do not provide useful biomarkers for the diagnosis of ME/CFS.

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Cytotoxic T lymphocyte effector function is independent of nucleus-centrosome dissociation.

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