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Plasma Membrane Organisation

Ingela Parmryd

Contact information  |  List of publications

The Functional Organisation of the Plasma Membrane in T cell Signalling

The plasma membrane of eukaryotic cells contains nanodomains, commonly referred to as lipid rafts, which are more ordered than the rest of the plasma membrane. The high order is generally considered equivalent to the tight packing of cholesterol and sphingolipids observed in model membranes. However, we have demonstrated that lipid rafts form when actin filaments are pinned to the plasma membrane via phosphoinositides and when extracellularly exposed receptors are pinned by antibodies (Dinic et al., 2013), suggesting that the mechanism for lipid raft formation is lipid-protein interactions. We have shown that T cell signalling is initiated upon lipid raft aggregation that can be triggered by cold stress and changes in the plasma membrane lipid composition (Magee et al., 2005; Mahammad et al. 2010).  We have recently shown that the T cell receptor in resting T cells resides in lipid rafts that are brought together upon receptor engagement (Dinic et al., 2015). We are now investigating what is triggering the formation of lipid rafts in more detail and how membrane order affects the molecular clustering that accompanies T cell signalling using techniques like super resolution microscopy and fluorescence correlation spectroscopy. The cell studies are accompanied by the development of methods for cluster analysis.

Cell Topography and Plasma Membrane Models

The cell surface is neither flat nor smooth but surface topography is ignored in current models of the plasma membrane. Using high resolution topographical maps of live cells, we and our collaborators have demonstrated that apparent topographical trapping is easily mistaken for elaborate membrane model features like hop diffusion and transient anchorage (Adler et al., 2010). Even binding could be the result of apparent topographical trapping when single particle tracks are interpreted in 2D although the molecules are moving in 3D. We have recently shown that ignoring membrane topography cause consistent underestimation of diffusion and that membrane topography itself can cause anomalous diffusion. Our conclusion is that disentangling apparent from genuine diffusion requires surface characterisation (Adler et al., 2018). We are now moving from simulations to cell images.

Different measures of movement in  a folded membrane
Different measures of movement in  a folded membrane. Using conventional  2D and 3D analysis methods allows the molecule to leave the membrane. This is an unlikely scenario. The movement needs to be analysed using the shortest within surface distance.

 

 

 

 

 

Image Analysis

We develop image analysis software to get quantitative and objective answers to biological questions. We have developed and patented the method RBNCC (replicate based noise corrected correlation) where image noise, which is unavoidable and leads to the underestimation of the underlying correlation, can be eliminated from correlation measurements (Adler et al. 2008).  We have performed detailed studies on coefficients developed for use in colocalisation analyses revealing that several are of doubtful use (Adler & Parmryd, 2010; Adler & Parmryd, 2018). We were the first to advocate that colocalisation analysis should be divided into the two subgroups co-occurrence and correlation (Adler & Parmryd, 2007; Adler & Parmryd, 2013) and that only pixels where both fluorophores are present should be included in correlation analyses (Adler et al. 2008; Adler & Parmryd, 2014). We now investigate how deconvolution affects correlation analysis and how different intracellular distributions of molecules are represented by our division of colocalisation analysis into co-occurrence and correlation.

Tumour cell-killing Vδ2Vγ9 T Cells

Vδ2Vγ9 T cells are a T cell subset that recognise and kill cancer cells that accumulate high levels of phosphoantigens, small organic compounds with phosphate groups. There is a positive correlation between the Vδ2Vγ9 T cell number and tumour cell death making Vδ2Vγ9 T cells appealing candidates for immunotherapy. A pilot study indicated that colon cancer patients have lower numbers of circulating Vδ2Vγ9 T cells than healthy individuals. Together with collaborators at the Uppsala University Hospital we address how the prevalence of Vδ2Vγ9 T cells in colon cancer patients at the four different cancer stages varies and characterise the Vδ2Vγ9 T cells regarding differentiation status, tumour homing potential, proliferation and cytotoxicity. Together with collaborators at Stockholm University we found that media from erythrocytes infected with P. falciparum can stimulate Vδ2Vγ9 T cell proliferation (Lindberg et al., 2013) suggesting that phosphoantigens both are produced in and released from these cells. In a recent study we show that this occurs at all parasite blood stages and not only, as previously thought, when the erythrocytes rupture and release parasites (Liu et al., 2018). We now address how the transport of phosphoantigens over membranes takes place. 

 

Group members

Ingela Parmryd, PhD, group leader, Associate Professor

Jeremy Adler, PhD, Research Engineer

 
 

 

Collaborations

Dr Ida-Maria Sintorn & Prof. Robin Strand, Centre for Image Analysis, Swedish University of Agricultural Sciences & Uppsala University

Dr Noushin S. Emami & Prof. Ingrid Faye, Department of Molecular Biosciences, Stockholm University

Dr Helgi Birgisson, Department of Surgical Sciences, Uppsala University Hospital

 

 

Sidansvarig: Dan Baeckström|Sidan uppdaterades: 2018-11-06
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