The Gaus Group want to know how T cells initiate an immune response.

The decision of a T cell to activate or not to activate is determined by a complex signalling network within the cells. In this network, information is encoded not only in the components, but also by the frequency and duration of their interactions.

Studying how individual molecules within the cell control the actions of T cells is a fundamental single molecule problem.

The Gaus Group is using new single molecule microscopes to understand the molecular basis of T cell decision-making, using strategies that combine mouse models with molecular biology, microscopy and mathematics (the 4 Ms).

Name
Position
Phone
Connect

The Gaus Group research focuses on developing new super-resolution fluorescence microscopes and analysis routines to understand the decision-making processes of T cells. Single molecule data provide a unique ‘bottom up’ perspective to T cell signalling networks in intact and live cells. With new analysis strategies, they can map where signalling begins and how signals spread through the cells. They also use nanotechnology to control where and when T cells are stimulated.

T cells can distinguish between peptides derived from damaged and infected cells such as cancer cells, and benign ‘self’ peptides derived from healthy cells. The T cell receptor binds to peptides bound to major histocompatibility complexes, so-called peptide-MHC (pMHC) complexes, on the surface of antigen presenting cells. Despite the relatively weak T cell receptor-pMHC binding affinity, T cells can sense and respond to even a single antigenic peptide. This can lead to effector functions including secretion of potent mediators and killing of infected or cancerous cells. However, there are many more self peptides than foreign peptides presented to T cells and in this case, the correct decision for the T cell is to do nothing at all.

Despite extensive experimental and mathematical work, we do not understand how pMHC recognition by the T cell receptor initiates intracellular signalling and how the signalling network processes information ultimately leading to T cell fate decisions. This is a central question in peptide-mediated immunity and vaccine development and could help us to identify new avenues for drug design to combat autoimmune diseases and agents for cancer immunotherapy.

“With new single molecule tools, and our formidable team, the only limit to what we can achieve is our imagination,” says Kat.

Research Themes

  • How does a T cell distinguish between peptides derived from “self” and “non-self”?
  • How does a single antigen recognition event lead to T cell activation?
  • Which antigen recognition event leads to immunological memory?
  • How do mechanical forces influence T cell receptor signalling?

 

Authors
Title
Published In

Ma Y, Yamamoto Y, Nicovich PR, Goyette J, Rossy J, Gooding JJ, Gaus K.

A FRET sensor enables quantitative measurements of membrane charges in live cells.

Nat Biotechnol. 2017 Mar 13. doi: 10.1038/nbt.3828. [Epub ahead of print]

Hinde E, Thammasiraphop K, Duong HT, Yeow J, Karagoz B, Boyer C, Gooding JJ*, Gaus K*.

Pair correlation microscopy reveals the role of nanoparticle shape in intracellular transport and site of drug release.

Nat Nanotechnol. 2016 Sep 12. doi: 10.1038/nnano.2016.160. [Epub ahead of print]

Abu-Siniyeh A, Owen DM, Benzing C, Rinkwitz S, Becker TS, Majumdar A, Gaus K.

The aPKC/Par3/Par6 Polarity Complex and Membrane Order Are Functionally Interdependent in Epithelia During Vertebrate Organogenesis.

Traffic. 2016 Jan;17(1):66-79. doi: 10.1111/tra.12339. Epub 2015 Nov 23.

Benda A, Ma Y, Gaus K.

Self-calibrated line-scan STED-FCS to quantify lipid dynamics in model and cell membranes.

Biophys J. 2015 Feb 3;108(3):596-609. doi: 10.1016/j.bpj.2014.12.007.

Cheng X, Hinde E, Owen DM, Lowe SB, Reece PJ, Gaus K, Gooding JJ.

Enhancing Quantum Dots for Bioimaging using Advanced Surface Chemistry and Advanced Optical Microscopy: Application to Silicon Quantum Dots (SiQDs).

Advanced Materials 2015;27(40):6144 - 6150. doi: http://dx.doi.org/10.1002/adma.201503223.

Pham S, Tabarin T, Garvey M, Pade C, Rossy J, Monaghan P, Hyatt A, Böcking T, Leis A, Gaus K, Mak J.

Cryo-electron microscopy and single molecule fluorescent microscopy detect CD4 receptor induced HIV size expansion prior to cell entry.

Virology. 2015 Dec;486:121-33. doi: 10.1016/j.virol.2015.09.006. Epub 2015 Sep 30.

Gupta B, Mai K, Lowe SB, Wakefield D, Di Girolamo N, Gaus K, Reece PJ, Gooding JJ.

Ultrasensitive and specific measurement of protease activity using functionalized photonic crystals.

Anal Chem. 2015 Oct 6;87(19):9946-53. doi: 10.1021/acs.analchem.5b02529. Epub 2015 Sep 8.

Yaffe Y, Hugger I, Yassaf IN, Shepshelovitch J, Sklan EH, Elkabetz Y, Yeheskel A, Pasmanik-Chor M, Benzing C, Macmillan A, Gaus K, Eshed-Eisenbach Y, Peles E, Hirschberg K.

The myelin proteolipid plasmolipin forms oligomers and induces liquid-ordered membranes in the Golgi complex.

J Cell Sci. 2015 Jul 1;128(13):2293-302. doi: 10.1242/jcs.166249. Epub 2015 May 22.

Gomez GA, McLachlan RW, Wu SK, Caldwell BJ, Moussa E, Verma S, Bastiani M, Priya R, Parton RG, Gaus K, Sap J, Yap AS.

An RPTPα/Src family kinase/Rap1 signaling module recruits myosin IIB to support contractile tension at apical E-cadherin junctions.

Mol Biol Cell. 2015 Apr 1;26(7):1249-62. doi: 10.1091/mbc.E14-07-1223. Epub 2015 Jan 28.

Ma Y, Hinde E, Gaus K.

Nanodomains in biological membranes.

Essays Biochem. 2015;57:93-107. doi: 10.1042/bse0570093.

Klotzsch E, Stiegler J, Ben-Ishay E, Gaus K.

Do mechanical forces contribute to nanoscale membrane organisation in T cells?

Biochim Biophys Acta. 2015 Apr;1853(4):822-9. doi: 10.1016/j.bbamcr.2014.10.025. Epub 2014 Nov 1.

Caldwell BJ, Lucas C, Kee AJ, Gaus K, Gunning PW, Hardeman EC, Yap AS, Gomez GA.

Tropomyosin isoforms support actomyosin biogenesis to generate contractile tension at the epithelial zonula adherens.

Cytoskeleton (Hoboken). 2014 Dec;71(12):663-76. doi: 10.1002/cm.21202. Epub 2015 Jan 31.

Alvarez-Guaita A, Vilà de Muga S, Owen DM, Williamson D, Magenau A, García-Melero A, Reverter M, Hoque M, Cairns R, Cornely R, Tebar F, Grewal T, Gaus K, Ayala-Sanmartín J, Enrich C, Rentero C.

Evidence for annexin A6-dependent plasma membrane remodelling of lipid domains.

Br J Pharmacol. 2015 Apr;172(7):1677-90. doi: 10.1111/bph.13022. Epub 2015 Jan 20.

Hinde E, Yokomori K, Gaus K, Hahn KM, Gratton E.

Fluctuation-based imaging of nuclear Rac1 activation by protein oligomerisation.

Sci Rep. 2014;4:4219. doi: 10.1038/srep04219. Epub2014 Feb 27.

Bach CT, Murray RZ, Owen D, Gaus K, O'Neill GM.

Tropomyosin tm5NM1 spatially restricts src kinase activity through perturbation of Rab11 vesicle trafficking.

Mol Cell Biol. 2014 Dec;34(24):4436–4446. doi: 10.1128/MCB.00796-14.

Kockx M, Karunakaran D, Traini M, Xue J, Huang KY, Nawara D, Gaus K, Jessup W, Robinson PJ, Kritharides L.

Pharmacological inhibition of dynamin II reduces constitutive protein secretion from primary human macrophages.

PLoS One. 2014 Oct 27;9(10):e111186. doi: 10.1371/journal.pone.0111186. eCollection 2014.

Lakshminarayan R, Wunder C, Becken U, Howes MT, Benzing C, Arumugam S, Sales S, Ariotti N, Chambon V, Lamaze C, Loew D, Shevchenko A, Gaus K, Parton RG, Johannes L.

Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers.

Nat Cell Biol. 2014 Jun;16(6):595-606. doi: 10.1038/ncb2970. Epub 2014 May 18.

Kwiatek JM, Hinde E, Gaus K.

Microscopy approaches to investigate protein dynamics and lipid organization.

Mol Membr Biol. 2014 Aug;31(5):141-51. doi: 10.3109/09687688.2014.937469. Epub 2014 Jul 21.

Guan B, Magenau A, Ciampi S, Gaus K, Reece PJ, Gooding JJ.

Antibody modified porous silicon microparticles for the selective capture of cells

Bioconjug Chem. 2014 Jul 16;25(7):1282-9. doi: 10.1021/bc500144u. Epub 2014 Jun 10.

Chockalingam M, Magenau A, Parker SG, Parviz M, Vivekchand SR, Gaus K, Gooding JJ.

Biointerfaces on indium-tin oxide prepared from organophosphonic acid self-assembled monolayers.

Langmuir. 2014 Jul 22;30(28):8509-15. doi: 10.1021/la501774b. Epub 2014 Jul 8.

Chaudhary N, Gomez GA, Howes MT, Lo HP, McMahon KA, Rae JA, Schieber NL, Hill MM, Gaus K, Yap AS, Parton RG.

Endocytic crosstalk: cavins, caveolins, and caveolae regulate clathrin-independent endocytosis.

PLoS Biol. 2014 Apr 8;12(4):e1001832. doi: 10.1371/journal.pbio.1001832. eCollection 2014.

Rossy J, Ma Y, Gaus K.

The organisation of the cell membrane: do proteins rule lipids?

Curr Opin Chem Biol. 2014 Jun;20:54-9. doi: 10.1016/j.cbpa.2014.04.009. Epub 2014 May 13.

Cheng X, Lowe SB, Ciampi S, Magenau A, Gaus K, Reece PJ, Gooding JJ.

Versatile "click chemistry" approach to functionalizing silicon quantum dots: applications toward fluorescent cellular imaging.

Langmuir. 2014 May 13;30(18):5209-16. doi: 10.1021/la500945f. Epub 2014 Apr 28.

Gambin Y, Ariotti N, McMahon KA, Bastiani M, Sierecki E, Kovtun O, Polinkovsky ME, Magenau A, Jung W, Okano S, Zhou Y, Leneva N, Mureev S, Johnston W, Gaus K, Hancock JF, Collins BM, Alexandrov K, Parton RG.

Single-molecule analysis reveals self assembly and nanoscale segregation of two distinct cavin subcomplexes on caveolae.

Elife. 2013 Jan 1;3:e01434. doi: 10.7554/eLife.01434.

Gooding JJ, Parker SG, Lu Y, Gaus K.

Molecularly engineered surfaces for cell biology: from static to dynamic surfaces.

Langmuir. 2014 Apr 1;30(12):3290-302. doi: 10.1021/la4037919. Epub 2013 Nov 22.

Rossy J, Cohen E, Gaus K, Owen DM.

Method for co-cluster analysis in multichannel single-molecule localisation data.

Histochem Cell Biol. 2014 Jun;141(6):605-12. doi: 10.1007/s00418-014-1208-z. Epub 2014 Mar 19.

Tabarin T, Pageon SV, Bach CT, Lu Y, O'Neill GM, Gooding JJ, Gaus K.

Insights into adhesion biology using single-molecule localization microscopy.

Chemphyschem. 2014 Mar 17;15(4):606-18. doi: 10.1002/cphc.201301041. Epub 2014 Feb 4.

Benda A, Kapusta P, Hof M, Gaus K.

Fluorescence spectral correlation spectroscopy (FSCS) for probes with highly overlapping emission spectra.

Opt Express. 2014 Feb 10;22(3):2973-88. doi: 10.1364/OE.22.002973.

Choi YI, Duke-Cohan JS, Chen W, Liu B, Rossy J, Tabarin T, Ju L, Gui J, Gaus K, Zhu C, Reinherz EL.

Dynamic control of β1 integrin adhesion by the plexinD1-sema3E axis.

Proc Natl Acad Sci U S A. 2014 Jan 7;111(1): 379–384. doi: 10.1073/pnas.1314209111. Epub 2013 Dec 16.

Ngalim SHA, Magenau A, Zhu Y, Tønnesen L, Fairjones Z, Gooding JJ, Böcking T, Gaus K.

Creating adhesive and soluble gradients for imaging cell migration with fluorescence microscopy.

J Vis Exp. 2013; (74): 50310. Epub 2013 Apr 4. doi: 10.3791/50310.

Owen DM, Gaus K.
 
 

Imaging lipid domains in cell membranes: the advent of super-resolution fluorescence microscopy.

Front Plant Sci. 2013 Dec 12;4:503. doi: 10.3389/fpls.2013.00503.

Owen DM, Magenau A, Williamson DJ, Gaus K.

Super-resolution imaging by localization microscopy.

Methods Mol Biol. 2013;950:81-93. doi: 10.1007/978-1-62703-137-0_6.

Rossy J, Owen DM, Williamson DJ, Yang Z, Gaus K.

Conformational states of the kinase Lck regulate clustering in early T cell signaling.

Nat Immunol. 2013 Jan;14(1):82-9. doi: 10.1038/ni.2488. Epub 2012 Dec 2.

Kwiatek JM, Owen DM, Abu-Siniyeh A, Yan P, Loew LM, Gaus K.

Characterization of a new series of fluorescent probes for imaging membrane order.

PLoS One. 2013;8(2):e52960. doi: 10.1371/journal.pone.0052960. Epub 2013 Feb 4.

Billcliff PG, Rollason R, Prior I, Owen DM, Gaus K, Banting G.

CD317/tetherin is an organiser of membrane microdomains.

J Cell Sci. 2013 Apr 1;126(Pt 7):1553-64. doi: 10.1242/jcs.112953. Epub 2013 Feb 1.

Larghi P, Williamson DJ, Carpier JM, Dogniaux S, Chemin K, Bohineust A, Danglot L, Gaus K, Galli T, Hivroz C.

VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites.

Nat Immunol. 2013 Jul;14(7):723-31. doi: 10.1038/ni.2609. Epub 2013 May 12.

Owen DM, Williamson DJ, Boelen L, Magenau A, Rossy J, Gaus K.
 

Quantitative analysis of three-dimensional fluorescence localization microscopy data.

Biophys J. 2013 Jul 16;105(2):L05-7. doi: 10.1016/j.bpj.2013.05.063.

Benzing C, Rossy J, Gaus K.

Do signalling endosomes play a role in T cell activation?

FEBS J. 2013 Nov;280(21):5164-76. doi: 10.1111/febs.12427. Epub 2013 Jul 26.

Rossy J, Pageon SV, Davis DM, Gaus K.

Super-resolution microscopy of the immunological synapse.

Curr Opin Immunol. 2013 Jun;25(3):307-12. doi: 10.1016/j.coi.2013.04.002. Epub 2013 Jun 7.

Rossy J, Williamson DJ, Gaus K.

How does the kinase Lck phosphorylate the T cell receptor? Spatial organization as a regulatory mechanism.

Front Immunol. 2012 Jun 19;3:167. doi: 10.3389/fimmu.2012.00167. eCollection 2012.

Owen DM, Rentero C, Magenau A, Abu-Siniyeh A, Gaus K.

Quantitative imaging of membrane lipid order in cells and organisms.

Nat Protoc. 2011 Dec 8;7(1):24-35. doi: 10.1038/nprot.2011.419.

Böcking T; Kilian KA; Reece PJ; Gaus K; Gal M; Gooding JJ, 2012, '', Soft Matter, vol. 8, no. 2, pp. 360 - 366, http://dx.doi.org/10.1039/c1sm06651j

Biofunctionalization of free-standing porous silicon films for self-assembly of photonic devices.

Soft Matter. 2012(8):360-366. doi: 10.1039/C1SM06651J. Epub 25 Oct 2011.
 

Ciampi S, James M, Le Saux G, Gaus K, Justin Gooding J.

Electrochemical "switching" of Si(100) modular assemblies.

J Am Chem Soc. 2012 Jan 18;134(2):844-7. doi: 10.1021/ja210048x. Epub 2011 Dec 22.

Owen DM, Williamson D, Magenau A, Gaus K.

Optical techniques for imaging membrane domains in live cells (live-cell palm of protein clustering).

Methods Enzymol. 2012;504:221-35. doi: 10.1016/B978-0-12-391857-4.00011-2.

Cui HL, Grant A, Mukhamedova N, Pushkarsky T, Jennelle L, Dubrovsky L, Gaus K, Fitzgerald ML, Sviridov D, Bukrinsky M.

HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux.

J Lipid Res. 2012 Apr;53(4):696-708. doi: 10.1194/jlr.M023119. Epub 2012 Jan 19.

Pereira CF, Rossy J, Owen DM, Mak J, Gaus K.

HIV taken by STORM: Super-resolution fluorescence microscopy of a viral infection.

Virology Journal 2 May 2012;9:84. doi: 0.1186/1743-422X-9-84.