Research

Background
signaltransduct
Saez-Rodriguez et al. 2007 PLoS Comput.Biol.

The immune system has to discriminate pathogens (e.g. bacteria or viruses and cancerous cells) from healthy cells within our body. Foreign cells should be attacked and eliminated, whereas self-tissues should not be harmed. The main cell type involved in this decision is the T-cell.

T-cell activation is a complex process relying on multiple layers of tightly controlled intracellular signaling molecules, which form an intricate and dynamic network. Defects in this network can cause autoimmune responses that destroy normal body cells: Horror autotoxicus. This term was coined by the bacteriologist and immunologist Paul Ehrlich (1854-1915) to describe the body's immunological self-destruction in severe disorders such as multiple sclerosis. In order to understand and predict the behaviour of this network it is therefore crucial to study it as a complete system and not only its isolated parts.

Scientific concept
carlos_formel

Through a multidisciplinary effort SYBILLA aims to understand at systems level, how T-cells discriminate foreign- from self-peptides by activating quantitatively distinct signaling pathways. Data obtained in mouse models are extended to human T cells and to a mouse model of multiple sclerosis.
SYBILLA develops new analytical and mathematical tools to generate and integrate high-density quantitative data describing T-cell activation. Proteomics, transcriptomics, imaging and biochemical techniques will be applied to obtain holistic maps of the T-cell signaling network and to achieve a quantitative and dynamic understanding of signaling networks and their regulation in response to different signal inputs.
Building upon already existing schemes of the network connectivity, constant iteration between experiment and mathematical modelling will be used to develop robust and predictive models that describe the functioning of the T-cell signaling network. SYBILLA will allow the identification of new drug targets and the discovery of new biomarkers to refine prognosis of autoimmune diseases.

Publications
Proteomics


A list of publications of the SYBILLA consortium can be seen in these tables here. Or you can downloaded them:



List of scientific publications of the SYBILLA consortium for 2012

Title

Peer-reviewed journal

Year

Relevant pages

Pubmed

Partners involved

T cell receptor (TCR)-induced tyrosine phosphorylation dynamics identifies THEMIS as a new TCR signalosome component.

JBC

2011

7535-47

PMID: 21189249

Acuto O,

UOXFa

Quantitative analysis of protein phosphorylations and interactions by multi-colour IP-FCM as an input for kinetic modelling of signalling networks.

PLoS ONE

2011

e22928

PMID: 21829558

Höfer T, DKFZ

Schamel W, MPI-IB

Integrating signals from the T-cell receptor and the interleukin-2 receptor

PLoS Comput Biol

2011

e1002121

PMID: 21829342

Schraven B, Lindquist J, UNIMAG

Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes.

Immunity

2011

375-87

PMID: 21903423

 

Alarcon B, CSIC, Schamel W, MPI-IB

The balance of pro-inflammatory and trophic factors in multiple sclerosis patients: effects of acute relapse and immunomodulatory treatment

Mult Scler

2011

851-866

PMID: 21561957

 

Lindquist J, UNIMAG

Molecular T cell biology?-?basic and translational challenges in the twenty-first century.

Front Immunol

2011

ePub

PMID: 22566794

 

Acuto O,

UOXFa

LAT signaling pathology: an "autoimmune" condition without T cell self-reactivity.

Trends Immunol

2010

253-259

PMID: 20542732

 

Malissen B, CNRS

Signaling in thymic selection.

Curr Opin Immunol

2011

207-212

PMID: 21242076

 

Palmer E, UNIBAS

Quantitative proteomics analysis of the nuclear fraction of human CD4+ cells in the early phases of IL-4-induced Th2 differentiation.

Mol Cell Proteomics

2010

1937-1953

PMID: 20467038

 

Lahesmaa R, UTU

SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation.

Blood

2010

1443-1453

PMID: 20522714

 

Lahesmaa R, UTU

Structural characterization of the TCR complex by electron microscopy.

 

Int Immunol

2010

897-903

PMID: 21059766

 

Alarcon B, CSIC, Schamel W, MPI-IB

Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming.

Immunity

2010

852-862

PMID: 20620947

 

Lahesmaa R, UTU

A new vampire saga: the molecular mechanism of T cell trogocytosis.

Immunity

2011

151-153

PMID: 21867922

 

Schamel W, MPI-IB

Coronin 1A is an essential regulator of the TGFß receptor/SMAD3 signaling pathway in Th17 CD4(+) T cells.

J Autoimmun

2011

198-208

PMID: 21700422

 

Baier G, MUI

Synthetic immune signaling

Curr Opin Biotech

2012

1-5

PMID: 22326912

 

Schamel W,

Reth M, MPI-IB

TCR Nanoclusters as the Framework for Transmission of Conformational Changes and Cooperativity.

Front Immunol

2012

ePub

PMID: 22582078

 

Alarcon B, CSIC

T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis.

Immunity

2011

208-222

PMID: 21820331

 

Alarcon B, CSIC

Identification of early gene expression changes during human Th17 cell differentiation.

Blood

2012

ePub

PMID: 22544700

 

Lahesmaa R, UTU

A discrete affinity-driven elevation of ZAP-70 kinase activity initiates negative selection.

J Recept Signal Transduct Res

2012

430-443

PMID: 20945976

 

Palmer E, UNIBAS

Meeting report signal transduction meets systems biology.

Cell Commun Signal

2012

ePub

PMID: 22546078

 

Lindquist J, UNIMAG, Schamel W,

MPI-IB

Phosphoprotein associated with glycosphingolipid-enriched microdomains differentially modulates SRC kinase activity in brain maturation.

PLoS One

2011

e23978

PMID: 21915273

 

Lindquist J,

Schraven B, UNIMAG

The balance of pro-inflammatory and trophic factors in multiple sclerosis patients: effects of acute relapse and immunomodulatory treatment.

Mult Scler

2011

851-866

PMID: 21561957

 

Lindquist J,

UNIMAG

Serotonin-mediated tuning of human helper T cell responsiveness to the chemokine CXCL12.

PLoS One

2011

e22482

PMID: 21853036

 

Viola A,

FHR

The critical role of agrin in the hematopoietic stem cell niche.

Blood

2011

2733-2742

PMID: 21653324

 

Viola A,

FHR

Agrin is required for survival and function of monocytic cells.

Blood

2012

ePub

PMID: 22517892

 

Viola A,

FHR




List of scientific publications of the SYBILLA consortium for 2009 and 2010

Title

Journal

Year

Pages

Pubmed number

SYBILLA Partners

Quantitative interaction proteomics using mass spectrometry.

Nat Methods

2009

203-205

PMID: 19198594

Aebersold R, Gstaiger M. ETHZ

STAT6 deletion converts the Th2 inflammatory pathology afflicting Lat(Y136F) mice into a lymphoproliferative disorder involving Th1 and CD8 effector T cells.

J Immunol.

2009

2680-2689

PMID: 19234162

Malissen B Malissen M CNRS

T Cell-Mediated Autoimmune Disease Due to Low-Affinity Crossreactivity to Common Microbial Peptides.

Immunity

2009

348-357

PMID: 19303388

Fugger L. UOXF

PKC inhibitors: potential in T cell-dependent immune diseases.

Curr Opin Cell Biol

2009

262-267

PMID: 19195860

Baier G MUI

Loss of the LAT adaptor converts antigen­ responsive T cells into pathogenic effectors that function independently of the T cell receptor.

Immunity

2009

197-208

PMID: 19682930

Malissen B, CNRS

Lymphoproliferative disorders involving T helper effector cells with defective LAT signalosomes

Sem Immunopath.

2010

117-125

PMID: 20107804

Malissen B, CNRS

Signaling amplification at the immunological synapse.

Current Topics Microbiol Immunol

2010

109-122

PMID: 19960311

Viola A, FHR

Tunable chemokine production by antigen presenting dendritic cells in response to changes in regulatory T cell frequency in mouse reactive lymph nodes.

PLOSone

2009

4:e7696

PMID: 19893746

Viola A, FHR

A novel KIR-associated function: evidence that CpG DNA uptake and shuttling to early endosomes is mediated by KIR3DL2

Blood

2010

1637-1647

PMID: 20147700

Viola A, FHR

Constitutively active Lck in T cell drives antigen receptor signal transduction

Immunity

2010

766-777

PMID: 20541955

Viola A, FHR,

Acuto O, UOXFa, Fugger L. UOXFb,

Höfer T, DKFZ

PKC-theta Modulates the Strength of T Cell Responses by Targeting Cbl-b for Ubiquitination & Degradation

Science Signaling

2009

ra30

PMID: 19549985

Baier G. MUI

The potent protein kinase C selective inhibitor AEB071 (Sotrastaurin)represents a new class of immunosuppressive agents affecting early T cell activation

J Pharmacol Exp Ther.

2009

792-801

PMID: 19491325

Baier G. MUI

PKC theta cooperates with PKC alpha in alloimmune responses of T cells in vivo.

Mol Immunol

2009

2071-2079

PMID: 19356803

Baier G. MUI

(PKC inhibitors: potential in T cell-dependent immune diseases

Curr Opin Cell Biol.

2009

262-267

PMID: 19195860

Baier G, MUI

NFAT pulls the strings during CD4+ T helper cell effector functions.

Blood

2010

2989-2997

PMID: 20103781

Baier G. MUI

SATB1 dictates expression of multiple genes including IL-5 involved in human T helper cell differentiation

Blood

2010

1443-1453

PMID: 20522714

Lahesmaa R, UTU

Quantitative Proteomics Analysis of the Nuclear Fraction of Human CD4+ Cells in the Early Phases of IL-4 Induced Th2 Differentiation

Molec Cell Proteomics

2010

1937-1953

PMID: 20467038

Lahesmaa R, UTU

Analysis of novel phospho-ITAM specific antibodies in a S2 reconstitution system for TCR-CD3 signalling

Imm Lett

2010

43-50

PMID: 20005895

Schamel W, MPI-IB Suchanek M, EXBIO

Stoichiometry and intracellular fate of TRIM­containing TCR complexes

Cell Commun Signal

2010

8:5

PMID: 20298603

Schamel W, MPI-IB Schraven B, UNIMAG

Detection of phosphorylated T and B cell antigen receptor species by Phos-tag SDS-and Blue Native-PAGE

Imm Lett

2010

51-56

PMID: 20005898

Schamel W, MPI-IB

Das Imunsystem besser verstehen lernen

systembiologie.de

2010

51-55

 

Höfer T, DKFZ Lindquist J, Schraven B, UNIMAG

Schamel W, MPI-IB