Functional Implications of Plasma Membrane Condensation for T Cell Activation

Rentero, Carles; Zech, Tobias; Quinn, Carmel M.; Engelhardt, Karin R.; Williamson, David J.; Grewal, Thomas; Jessup, Wendy; Harder, Thomas; Gaus, Katharina

doi:10.1371/journal.pone.0002262

Cited by 99 publications

(112 citation statements)

References 46 publications

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“…We have previously reported that engagement and signaling through the TCR reorganizes the membrane at these sites to yield highly ordered domains (40). In addition, we observed a similar relationship as found in this study, in which ex vivo lipid manipulations of Jurkat T cells decrease the membrane order specifically at the T cell activation site, impairing IL-2 production and secretion (25).…”

Section: Discussionsupporting

confidence: 87%

“…We have previously shown that disrupting membrane condensation at the T cell activation site inhibits T cell signal transduction and downstream effector functions in vitro (25). In this study we examined the impact of dietary lipids on T cell lipid composition and membrane order and how this correlates to in vivo and ex vivo T cell responses, specifically in the absence of obesity and obesity-induced inflammation.…”

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confidence: 99%

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Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr−/− Mice

Pollock

Tedla

Hancock

et al. 2016

The Journal of Immunology

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Although it is recognized that lipids and membrane organization in T cells affect signaling and T cell activation, to what extent dietary lipids alter T cell responsiveness in the absence of obesity and inflammation is not known. In this study, we fed low-density lipoprotein receptor knockout mice a Western high-fat diet for 1 or 9 wk and examined T cell responses in vivo along with T cell lipid composition, membrane order, and activation ex vivo. Our data showed that high levels of circulating lipids for a prolonged period elevated CD4+ and CD8+ T cell proliferation and resulted in an increased proportion of CD4+ central-memory T cells within the draining lymph nodes following induction of contact hypersensitivity. In addition, the 9-wk Western high-fat diet elevated the total phospholipid content and monounsaturated fatty acid level, but decreased saturated phosphatidylcholine and sphingomyelin within the T cells. The altered lipid composition in the circulation, and of T cells, was also reflected by enhanced membrane order at the activation site of ex vivo activated T cells that corresponded to increased IL-2 mRNA levels. In conclusion, dietary lipids can modulate T cell lipid composition and responses in lipoprotein receptor knockout mice even in the absence of excess weight gain and a proinflammatory environment.

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Section: Discussionsupporting

confidence: 87%

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confidence: 99%

Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr−/− Mice

Pollock

Tedla

Hancock

et al. 2016

The Journal of Immunology

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“…That the T cell plasma membrane of fixed cells that are in contact with beads coated with anti--CD3 antibody is more ordered than the rest of the T cells plasma membrane, has been demonstrated by studying laurdan generalised polarisation [16,17]. In a very recent study by the same group, it was demonstrated that lipids expected to form lipid rafts like cholesterol, sphingomyelin and PC with saturated acyl chains accumulate where T cells interact with beads covered in antibodies against the T cell receptor [21].…”

Section: Discussionmentioning

confidence: 99%

“…If this holds for cell plasma membranes, cholesterol depletion could lead to the aggregation of lipid rafts. That cholesterol and the capability to form raft--like liquid ordered domains are important for membrane condensation (the existence of ordered domains), at the contact site between T cells and beads coated with T cell antigen receptor (TCR) stimulating antibodies, has been demonstrated in fixed cells [16,17].…”

Section: Introductionmentioning

confidence: 99%

Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation

Mahammad

Dinić

Adler

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Acute cholesterol depletion is generally associated with decreased or abolished T cell signalling but it can also cause T cell activation. This anomaly has been addressed in Jurkat T cells using progressive cholesterol depletion with methyl--beta--cyclodextrin (MBCD). At depletion levels higher than 50% there is substantial cell death, which explains reports of signalling inhibition. At 10--20% depletion levels, tyrosine phosphorylation is increased, ERK is activated and there is a small increase in cytoplasmic Ca 2+ . Peripheral actin polymerisation is also triggered by limited cholesterol depletion. Strikingly, the lipid raft marker GM1 aggregates upon cholesterol depletion and these aggregated domains concentrate the signalling proteins Lck and LAT, whereas the opposite is true for the non lipid raft marker the transferrin receptor. Using PP2, an inhibitor of Src family kinase activation, it is demonstrated that the lipid raft aggregation occurs independently of and thus upstream of the signalling response. Upon cholesterol depletion there is an increase in overall plasma membrane order, indicative of more liquid ordered domains forming at the expense of liquid disordered domains. That cholesterol depletion and not unspecific effects of MBCD was behind the reported results was confirmed by performing all experiments with MBCD--cholesterol, when no net cholesterol extraction took place. We conclude that non--lethal cholesterol depletion causes the aggregation of lipid rafts which then induces T cell signalling.

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“…A total of 10-20 circular areas per condition, corresponding to the ciliary base, were selected on the basis of galectin-3 staining. Generalized polarization values were non-linearly fitted to a Gauss distribution using a custom-built macro in ImageJ (Rentero et al, 2008).…”

Section: Laurdan Cell Microscopymentioning

confidence: 99%

The MAL protein is crucial for proper membrane condensation at the ciliary base, which is required for primary cilium elongation

Reales

Bernabé‐Rubio

Casares-Arias

et al. 2015

Journal of Cell Science

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The base of the primary cilium contains a zone of condensed membranes whose importance is not known. Here, we have studied the involvement of MAL, a tetraspanning protein that exclusively partitions into condensed membrane fractions, in the condensation of membranes at the ciliary base and investigated the importance of these membranes in primary cilium formation. We show that MAL accumulates at the ciliary base of epithelial MDCK cells. Knockdown of MAL expression resulted in a drastic reduction in the condensation of membranes at the ciliary base, the percentage of ciliated cells and the length of the cilia, but did not affect the docking of the centrosome to the plasma membrane or produce missorting of proteins to the pericentriolar zone or to the membrane of the remaining cilia. Rab8 (for which there are two isoforms, Rab8A and Rab8b), IFT88 and IFT20, which are important components of the machinery of ciliary growth, were recruited normally to the ciliary base of MAL-knockdown cells but were unable to elongate the primary cilium correctly. MAL, therefore, is crucial for the proper condensation of membranes at the ciliary base, which is required for efficient primary cilium extension.

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Functional Implications of Plasma Membrane Condensation for T Cell Activation

Cited by 99 publications

References 46 publications

Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr−/− Mice

Prolonged Intake of Dietary Lipids Alters Membrane Structure and T Cell Responses in LDLr−/− Mice

Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation

The MAL protein is crucial for proper membrane condensation at the ciliary base, which is required for primary cilium elongation

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