Dataset Information

Communication of CD8⁺ T cells with mononuclear phagocytes in multiple sclerosis.

ABSTRACT:

Objective

CD8⁺ T cells are the most prevailing lymphocyte population in inflammatory lesions of patients with multiple sclerosis (MS) but it is not even known whether they are merely passive bystanders or actively communicate with other cells in the brain. To identify their potential interaction partners, we analyzed CD8⁺ T cells that contained vectorially oriented cytotoxic granules and analyzed the areas to which the granules pointed.

Methods

We stained cryo-sections of active MS lesions of an index patient with antibodies to CD8 and perforin, searched for vectorially oriented perforin granules, and isolated target areas opposing the granules and control areas by laser-microdissection. From both areas, we analyzed cell-type specific transcripts by next-generation sequencing. In parallel, we stained samples from the index-patient and other patients by four-color immunohistochemistry (IHC).

Results

We found transcripts of the mononuclear phagocyte (MP) specific markers CD163 and CD11b only in the microdissected target areas but not in control areas. We validated the finding that MPs are communication partners of CD8⁺ T cells in MS lesions by classical IHC in samples from the index-patient and other patients with acute and progressive MS and other inflammatory neurological diseases.

Interpretation

Because CD163 and CD11b are specifically expressed in MPs, our findings suggest that CD8⁺ T cells communicate with local MPs. Although it is still unclear if these interactions lead to killing of the communication partners by CD8⁺ T cells, our data underline that CD8⁺ T cells play an active role in the pathogenesis of MS.

SUBMITTER: Konjevic Sabolek M

PROVIDER: S-EPMC6649540 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Communication of CD8<sup>+</sup> T cells with mononuclear phagocytes in multiple sclerosis.

Konjevic Sabolek Matea M Held Kathrin K Beltrán Eduardo E Niedl Anna G AG Meinl Edgar E Hohlfeld Reinhard R Lassmann Hans H Dornmair Klaus K

Annals of clinical and translational neurology 20190614 7

<h4>Objective</h4>CD8<sup>+</sup> T cells are the most prevailing lymphocyte population in inflammatory lesions of patients with multiple sclerosis (MS) but it is not even known whether they are merely passive bystanders or actively communicate with other cells in the brain. To identify their potential interaction partners, we analyzed CD8<sup>+</sup> T cells that contained vectorially oriented cytotoxic granules and analyzed the areas to which the granules pointed.<h4>Methods</h4>We stained cry ...[more]

PMID: 31353869

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Project description:Porcine reproductive and respiratory syndrome virus (PRRSV) is a positive-stranded RNA virus, which emerged in Europe and U.S.A. in the late 1980s and has since caused huge economic losses. Infection with PRRSV causes mild to severe respiratory and reproductive clinical symptoms in pigs. Alteration of the host immune response by PRRSV is associated with the increased susceptibility to secondary viral and bacterial infections resulting in more serious and chronic disease. However, the expression profiles underlying innate and adaptive immune responses to PRRSV infection are yet to be further elucidated. In this study, we investigated gene expression profiles of PBMCs and CD8+ T cells after PRRSV AUT15-33 infection. We identified the highest number of differentially expressed genes in PBMCs and CD8+ T cells at 7 dpi and 21 dpi, respectively. The gene expression profile of PBMCs from infected animals was dominated by a strong innate immune response at 7 dpi which persisted through 14 dpi and 21 dpi and was accompanied by involvement of adaptive immunity. The gene expression pattern of CD8+ T cells showed a strong adaptive immune response to PRRSV, leading to the formation of highly differentiated CD8+ T cells starting from 14 dpi. The hallmark of the CD8+ T-cell response was the increased expression of effector and cytolytic genes (PRF1, GZMA, GZMB, GZMK, KLRK1, KLRD1, FASL, NKG7), with the highest levels observed at 21 dpi. Temporal clustering analysis of DEGs of PBMCs and CD8+ T cells from PRRSV-infected animals revealed three and four clusters, respectively, suggesting tight transcriptional regulation of both the innate and the adaptive immune response to PRRSV. The main cluster of PBMCs was related to the innate immune response to PRRSV, while the main clusters of CD8+ T cells represented the initial transformation and differentiation of these cells in response to the PRRSV infection. Together, we provided extensive transcriptomics data explaining gene signatures of the immune response of PBMCs and CD8+ T cells after PRRSV infection. Additionally, our study provides potential biomarker targets useful for vaccine and therapeutics development.

Project description:BACKGROUND:Multiple sclerosis (MS) is characterized by increased activation of peripheral blood mononuclear cells (PBMCs), linked to perturbations in the phosphorylation of signaling proteins. METHODS:We developed a phosphoflow cytometry protocol to assess the levels of 11 phosphorylated nuclear proteins at baseline conditions and after cell activation in distinct PBMC populations from 41 treatment-naïve relapsing-remitting (RR) MS subjects and 37 healthy controls, and in a second cohort of 9 untreated RRMS patients and 10 secondary progressive (SP) MS patients. Levels of HLA-ABC, HLA-E, and HLA-DR were also assessed. Phosphorylation levels of selected proteins were also assessed in mouse splenocytes isolated from myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE). RESULTS:Modest differences were observed at baseline between patients and controls, with general lower phosphorylation levels in cells from affected individuals. Conversely, a dramatic increase in phosphorylated p38MAPK and STAT proteins was observed across all cell types in MS patients compared to controls after in vitro activation. A similar phosphorylation profile was observed in mouse lymphocytes primed in vivo with MOG. Furthermore, levels of all p-STAT proteins were found directly correlated with HLA expression in monocytes. Levels of phosphorylated proteins did not differ between relapsing-remitting and secondary progressive MS patients either in baseline conditions or after stimulation. Lastly, phosphorylation levels appear to be independent of the genotype. CONCLUSION:The response to IFN-? through STAT proteins signaling is strongly dysregulated in MS patients irrespective of disease stage. These findings suggest that the aberrant activation of this pathway could lead to changes in the expression of HLA molecules in antigen presenting cells, which are known to play important roles in the regulation of the immune response in health and disease.

Dataset Information

Communication of CD8⁺ T cells with mononuclear phagocytes in multiple sclerosis.

Objective

Methods

Results

Interpretation

Publications

Communication of CD8<sup>+</sup> T cells with mononuclear phagocytes in multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Communication of CD8+ T cells with mononuclear phagocytes in multiple sclerosis.

Objective

Methods

Results

Interpretation

Publications

Communication of CD8<sup>+</sup> T cells with mononuclear phagocytes in multiple sclerosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Communication of CD8⁺ T cells with mononuclear phagocytes in multiple sclerosis.