Integrative mapping of lymphocyte signaling and function

Coordinator : R. Lesourne / L.Dupré

Scientific objectives


A critical component of the immunological response to foreign protein is the activation of T lymphocytes. T-cell receptor (TCR) recognition of peptide loaded-histocompatibility molecules (MHC) provides antigen specificity and initiates the required steps for T-cell activation and differentiation into T cell subsets with specific and adapted immune function. The recognition of peptide-MHC complexes by TCRs triggers the activation of a complex network of intracellular signaling pathways. The quality, the duration and the strength of these signals determine the outcome of T cell responses and is therefore critical for 1) the discrimination between self and non self antigens, 2) the generation and expansion of the appropriate functional T cell subsets, 3) the control of pathological disorders.

La signalisation par les TCR et ses co-récepteurs détermine les réponses des lymphocytes T

The aim of our research is to identify new molecular mechanisms involved in T cell signaling and to investigate their functional consequences on T cell responses during physiological or pathophysiological processes such as immunodeficiencies and autoimmune and disorders. Our experimental strategy is on one hand to use integrative approaches such as mass spectrometry to establish a molecular mapping of signaling networks involved in T cell activation. And on the other hand, to analyze lymphocytes from patients suffering from rare immunodeficiencies and use genetically engineered mice models to elucidate the specific function of components of these networks. Our research activity is mainly focused on molecular events associated to the T cell receptor signaling and to the remolding of actin cytoskeleton during the dynamic steps of T cell biology.

Other information


Societal impact

Numerous primary immunodeficiencies results from mutations on genes encoding for signalling molecules that control T cell development and function. The molecular mechanism by which many of these molecules and mutations operate remains unknown. Beyond these rare pathologies, the susceptibility to many and more frequent diseases results from the combined association of genetic variants affecting the expression and function of signalling molecules involved in T cell activation.

These defects can trigger uncontrolled reactions of T lymphocytes against healthy cells (diabetes, multiple sclerosis) or against generally harmless environmental factors (allergy). On the contrary, in some pathology they can prevent efficient T cell-dependent immune reaction (cancers). Some virus (like the HIV) or pathogenic bacteria also divert T cell signaling pathways to inhibit or control immune responses in their advantages. Understanding T cell signaling is therefore a major challenge to determine the etiology of several human pathologies and to facilitate the development of specific therapy.

 

Publications

2018

Houmadi, R; Guipouy, D; Rey-Barroso, J; Vasconcelos, Z; Cornet, J; Manghi, M; Destainville, N; Valitutti, S; Allart, S; Dupre, L

The Wiskott-Aldrich Syndrome Protein Contributes to the Assembly of the LFA-1 Nanocluster Belt at the Lytic Synapse Journal Article

Cell Rep, 22 (4), pp. 979-991, 2018, ISSN: 2211-1247 (Electronic).

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Gaud, G; Lesourne, R; Love, P E

Regulatory mechanisms in T cell receptor signalling Journal Article

Nat Rev Immunol, 2018, ISSN: 1474-1741 (Electronic) 1474-1733 (Linking).

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Rey-Barroso, Javier; Calovi, Daniel S; Combe, Maud; German, Yolla; Moreau, Mathieu; Canivet, Astrid; Wang, Xiaobo; Sire, Clément; Theraulaz, Guy; Dupré, Loïc

Switching between individual and collective motility in B lymphocytes is controlled by cell-matrix adhesion and inter-cellular interactions Journal Article

Scientific Reports, 8 (1), pp. 5800, 2018, ISSN: 2045-2322.

Abstract | Links | BibTeX

2017

Duguet, F; Locard-Paulet, M; Marcellin, M; Chaoui, K; Bernard, I; Andreoletti, O; Lesourne, R; Burlet-Schiltz, O; Gonzalez de Peredo, A; Saoudi, A

Proteomic Analysis of Regulatory T Cells Reveals the Importance of Themis1 in the Control of Their Suppressive Function Journal Article

Mol Cell Proteomics, 16 (8), pp. 1416-1432, 2017, ISSN: 1535-9484 (Electronic) 1535-9476 (Linking).

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Cheng, D; Deobagkar-Lele, M; Zvezdova, E; Choi, S; Uehara, S; Baup, D; Bennett, S C; Bull, K R; Crockford, T L; Ferry, H; Warzecha, C; Marcellin, M; de Peredo, A G; Lesourne, R; Anzilotti, C; Love, P E; Cornall, R J

Themis2 lowers the threshold for B cell activation during positive selection Journal Article

Nat Immunol, 18 (2), pp. 205-213, 2017, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

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Choi, S; Cornall, R; Lesourne, R; Love, P E

THEMIS: Two Models, Different Thresholds Journal Article

Trends Immunol, 38 (9), pp. 622-632, 2017, ISSN: 1471-4981 (Electronic) 1471-4906 (Linking).

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Choi, S; Warzecha, C; Zvezdova, E; Lee, J; Argenty, J; Lesourne, R; Aravind, L; Love, P E

THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1 Journal Article

Nat Immunol, 18 (4), pp. 433-441, 2017, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

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Combedazou, A; Choesmel-Cadamuro, V; Gay, G; Liu, J; Dupre, L; Ramel, D; Wang, X

Myosin II governs collective cell migration behaviour downstream of guidance receptor signalling Journal Article

J Cell Sci, 130 (1), pp. 97-103, 2017, ISSN: 1477-9137 (Electronic) 0021-9533 (Linking).

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Cotta-de-Almeida, V; Dupre, L; Savino, W

Editorial: T-Cell Migration in Health and Disease Journal Article

Front Immunol, 8 , pp. 132, 2017, ISSN: 1664-3224 (Print) 1664-3224 (Linking).

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Garreau, A; Blaize, G; Argenty, J; Rouquie, N; Tourdes, A; Wood, S A; Saoudi, A; Lesourne, R

Grb2-Mediated Recruitment of USP9X to LAT Enhances Themis Stability following Thymic Selection Journal Article

J Immunol, 2017, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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Pfajfer, L; Seidel, M G; Houmadi, R; Rey-Barroso, J; Hirschmugl, T; Salzer, E; Anton, I M; Urban, C; Schwinger, W; Boztug, K; Dupre, L

WIP deficiency severely affects human lymphocyte architecture during migration and synapse assembly Journal Article

Blood, 130 (17), pp. 1949-1953, 2017, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

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Sarkar, K; Han, S S; Wen, K K; Ochs, H D; Dupre, L; Seidman, M M; Vyas, Y M

R-loops cause genomic instability in T helper lymphocytes from patients with Wiskott-Aldrich syndrome Journal Article

J Allergy Clin Immunol, 2017, ISSN: 1097-6825 (Electronic) 0091-6749 (Linking).

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2016

Salzer, E; Cagdas, D; Hons, M; Mace, E M; Garncarz, W; Petronczki, O Y; Platzer, R; Pfajfer, L; Bilic, I; Ban, S A; Willmann, K L; Mukherjee, M; Supper, V; Hsu, H T; Banerjee, P P; Sinha, P; McClanahan, F; Zlabinger, G J; Pickl, W F; Gribben, J G; Stockinger, H; Bennett, K L; Huppa, J B; Dupre, L; Sanal, O; Jager, U; Sixt, M; Tezcan, I; Orange, J S; Boztug, K

RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics Journal Article

Nat Immunol, 17 (12), pp. 1352-1360, 2016, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

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Zvezdova, E; Mikolajczak, J; Garreau, A; Marcellin, M; Rigal, L; Lee, J; Choi, S; Blaize, G; Argenty, J; Familiades, J; Li, L; Gonzalez de Peredo, A; Burlet-Schiltz, O; Love, P E; Lesourne, R

Themis1 enhances T cell receptor signaling during thymocyte development by promoting Vav1 activity and Grb2 stability Journal Article

Sci Signal, 9 (428), pp. ra51, 2016, ISSN: 1937-9145 (Electronic) 1945-0877 (Linking).

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2015

Amin, R; Mourcin, F; Uhel, F; Pangault, C; Ruminy, P; Dupre, L; Guirriec, M; Marchand, T; Fest, T; Lamy, T; Tarte, K

DC-SIGN-expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma Journal Article

Blood, 126 (16), pp. 1911-20, 2015, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

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Christophe, C; Muller, S; Rodrigues, M; Petit, A E; Cattiaux, P; Dupre, L; Gadat, S; Valitutti, S

A biased competition theory of cytotoxic T lymphocyte interaction with tumor nodules Journal Article

PLoS One, 10 (3), pp. e0120053, 2015, ISSN: 1932-6203 (Electronic) 1932-6203 (Linking).

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Cotta-de-Almeida, V; Dupre, L; Guipouy, D; Vasconcelos, Z

Signal Integration during T Lymphocyte Activation and Function: Lessons from the Wiskott-Aldrich Syndrome Journal Article

Front Immunol, 6 , pp. 47, 2015, ISSN: 1664-3224 (Print) 1664-3224 (Linking).

Links | BibTeX

Dupre, L; Houmadi, R; Tang, C; Rey-Barroso, J

T Lymphocyte Migration: An Action Movie Starring the Actin and Associated Actors Journal Article

Front Immunol, 6 , pp. 586, 2015, ISSN: 1664-3224 (Print) 1664-3224 (Linking).

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Malet-Engra, G; Yu, W; Oldani, A; Rey-Barroso, J; Gov, N S; Scita, G; Dupre, L

Collective cell motility promotes chemotactic prowess and resistance to chemorepulsion Journal Article

Curr Biol, 25 (2), pp. 242-50, 2015, ISSN: 1879-0445 (Electronic) 0960-9822 (Linking).

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Pedros, C; Gaud, G; Bernard, I; Kassem, S; Chabod, M; Lagrange, D; Andreoletti, O; Dejean, A S; Lesourne, R; Fournie, G J; Saoudi, A

An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development Journal Article

J Immunol, 195 (4), pp. 1608-16, 2015, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

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Vasconcelos, Z; Muller, S; Guipouy, D; Yu, W; Christophe, C; Gadat, S; Valitutti, S; Dupre, L

Individual Human Cytotoxic T Lymphocytes Exhibit Intraclonal Heterogeneity during Sustained Killing Journal Article

Cell Rep, 11 (9), pp. 1474-85, 2015, ISSN: 2211-1247 (Electronic).

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INSERM

INSERM

ARSEP

ARSEP

CNRS

CNRS

Université Toulouse Paul Sabatier

Université Toulouse Paul Sabatier

Région Occitanie

Région Occitanie

Fondation ARC

Fondation ARC

Seventh Framework Programme

Seventh Framework Programme