A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells

Quann, Emily J.; Liu, Xin; Altan‐Bonnet, Grégoire; Huse, Morgan

doi:10.1038/ni.2033

Cited by 140 publications

(183 citation statements)

References 44 publications

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“…Even normal regulation itself of TCR-induced lytic granule trafficking in CD8 + T cells is not fully understood (28)(29)(30). Our findings suggest several plausible hypotheses, however.…”

Section: Discussioncontrasting

confidence: 40%

Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

Lee

Wondimu

Liu

et al. 2012

The Journal of Immunology

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Granule exocytosis-mediated cytotoxicity by CD8+ CTL plays a crucial role in adaptive immunity to tumors and to intracellular pathogens. This T cell effector function has been shown to be defective in various murine tumor models and in human cancer. However, factors and their mechanisms that cause inhibition of CD8+ T cell lytic function in tumor-bearing hosts remain to be fully defined. We postulate that gangliosides, highly expressed on tumor cell membranes, actively shed into the tumor microenvironment, and having well-established immunosuppressive properties, may be such a factor. We exposed primary mouse CD8+ CTL to gangliosides derived from three sources (tumors and normal brain). This significantly inhibited cytotoxicity-mediated by granule exocytosis, that is, cytotoxicity of alloantigen-specific and polyclonal CD8+ CTL in vitro. These molecules did not interfere with the interaction of CD8+ T cells with their cognate targets. Rather, they inhibited lytic granule release in response both to TCR engagement and to stimuli that induce granule release in a nonpolarized manner. At the subcellular level, confocal microscopic imaging identified inhibition of polarization of lytic granules to the immunological synapse upon target cell recognition. Thus, tumor-shed gangliosides suppress lytic activity of CD8+ T cells by a novel mechanism, that is, inhibition of trafficking of lytic granules in response to TCR engagement, as well as by interfering with the process of granule exocytosis in CD8+ T cells.

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“…Even normal regulation itself of TCR-induced lytic granule trafficking in CD8 + T cells is not fully understood (28)(29)(30). Our findings suggest several plausible hypotheses, however.…”

Section: Discussioncontrasting

confidence: 40%

Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

Lee

Wondimu

Liu

et al. 2012

The Journal of Immunology

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“…2D, top and middle panels). Because redundancy and/or synergy has been reported for PKCs in different cell types (including T lymphocytes), and thus may require inhibition of more than one isoform (33)(34)(35), we transfected cells with a combination of siRNAs to PKC isoforms (i.e., PKC a/b, PKC d/u, PKC ε/u, and PKC h/u), but again found no obvious role for these PKCs in L-plastin phosphorylation (Fig. 2D, bottom panel).…”

Section: Resultsmentioning

confidence: 99%

L-Plastin Regulates Polarization and Migration in Chemokine-Stimulated Human T Lymphocytes

Freeley

O’Dowd

Paul

et al. 2012

The Journal of Immunology

105

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Chemokines such as SDF-1α play a crucial role in orchestrating T lymphocyte polarity and migration via polymerization and reorganization of the F-actin cytoskeleton, but the role of actin-associated proteins in this process is not well characterized. In this study, we have investigated a role for L-plastin, a leukocyte-specific F-actin–bundling protein, in SDF-1α–stimulated human T lymphocyte polarization and migration. We found that L-plastin colocalized with F-actin at the leading edge of SDF-1α–stimulated T lymphocytes and was also phosphorylated at Ser5, a site that when phosphorylated regulates the ability of L-plastin to bundle F-actin. L-plastin phosphorylation was sensitive to pharmacological inhibitors of protein kinase C (PKC), and several PKC isoforms colocalized with L-plastin at the leading edge of SDF-1α–stimulated lymphocytes. However, PKC ζ, an established regulator of cell polarity, was the only isoform that regulated L-plastin phosphorylation. Knockdown of L-plastin expression with small interfering RNAs demonstrated that this protein regulated the localization of F-actin at the leading edge of chemokine-stimulated cells and was also required for polarization, lamellipodia formation, and chemotaxis. Knockdown of L-plastin expression also impaired the Rac1 activation cycle and Akt phosphorylation in response to SDF-1α stimulation. Furthermore, L-plastin also regulated SDF-1α–mediated lymphocyte migration on the integrin ligand ICAM-1 by influencing velocity and persistence, but in a manner that was independent of LFA-1 integrin activation or adhesion. This study, therefore, demonstrates an important role for L-plastin and the signaling pathways that regulate its phosphorylation in response to chemokines and adds L-plastin to a growing list of proteins implicated in T lymphocyte polarity and migration.

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“…The top-ranked super-enhancer in both IEL populations is adjacent to Prkch (Fig. S3B), a nonclassical Ca2 + -insensitive η-type PKC that promotes T-cell activation and cytoskeletal polarization (14,15).…”

Section: Significancementioning

confidence: 99%

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

Semenkovich

Planer

Griffin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ + and γδ + intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.gut microbiota-immune cell interactions | ATAC-seq | enhancers of gut intraepithelial lymphocytes | transcription factors | gnotobiotic mice

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A cascade of protein kinase C isozymes promotes cytoskeletal polarization in T cells

Cited by 140 publications

References 44 publications

Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

Ganglioside Inhibition of CD8+ T Cell Cytotoxicity: Interference with Lytic Granule Trafficking and Exocytosis

L-Plastin Regulates Polarization and Migration in Chemokine-Stimulated Human T Lymphocytes

Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

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