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.




Donnadieu, Emmanuel ; Dupré, Loïc ; Pinho, Lia Gonçalves ; Cotta-de-Almeida, Vinicius

Surmounting the obstacles that impede effective CAR Ŧ cell trafficking to solid tumors Journal Article

Journal of Leukocyte Biology, 2020, ISSN: 1938-3673.

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German, Yolla ; Vulliard, Loan ; Rubio, Aude ; Boztug, Kaan ; Ferrand, Audrey ; Menche, Jörg ; Dupré, Loïc

Morphological profiling of human Ŧ and NK lymphocytes identifies actin-mediated control of the immunological synapse Journal Article

bioRxiv, pp. 2020.01.17.910091, 2020.

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Gallais, Fanny ; Ysebaert, Loïc ; Despas, Fabien ; De Barros, Sandra ; Dupré, Loïc ; Quillet-Mary, Anne ; Protin, Caroline ; Thomas, Fabienne ; Obéric, Lucie ; Allal, Ben ; Chatelut, Etienne ; White-Koning, Mélanie

Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies Journal Article

Clinical Pharmacokinetics, 2020, ISSN: 1179-1926.

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Thian, Marini ; Hoeger, Birgit ; Kamnev, Anton ; Poyer, Fiona ; Köstel Bal, Sevgi ; Caldera, Michael ; Jiménez-Heredia, Raúl ; Huemer, Jakob ; Pickl, Winfried F; Groß, Miriam ; Ehl, Stephan ; Lucas, Carrie L; Menche, Jörg ; Hutter, Caroline ; Attarbaschi, Andishe ; Dupré, Loïc ; Boztug, Kaan

Germline biallelic PIK3CG mutations in a multifaceted immunodeficiency with immune dysregulation Journal Article

Haematologica, 2020, ISSN: 1592-8721.

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Blaize, Gaëtan ; Daniels-Treffandier, Hélène ; Aloulou, Meryem ; Rouquié, Nelly ; Yang, Cui ; Marcellin, Marlène ; Gador, Mylène ; Benamar, Mehdi ; Ducatez, Mariette ; Song, Ki-Duk ; Burlet-Schiltz, Odile ; Saoudi, Abdelhadi ; Love, Paul E; Fazilleau, Nicolas ; Gonzalez de Peredo, Anne ; Lesourne, Renaud

CD5 signalosome coordinates antagonist TCR signals to control the generation of Treg cells induced by foreign antigens Journal Article

Proceedings of the National Academy of Sciences of the United States of America, 2020, ISSN: 1091-6490.

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Salzer, Elisabeth ; Zoghi, Samaneh ; Kiss, Máté G; Kage, Frieda ; Rashkova, Christina ; Stahnke, Stephanie ; Haimel, Matthias ; Platzer, René ; Caldera, Michael ; Ardy, Rico Chandra ; Hoeger, Birgit ; Block, Jana ; Medgyesi, David ; Sin, Celine ; Shahkarami, Sepideh ; Kain, Renate ; Ziaee, Vahid ; Hammerl, Peter ; Bock, Christoph ; Menche, Jörg ; Dupré, Loïc ; Huppa, Johannes B; Sixt, Michael ; Lomakin, Alexis ; Rottner, Klemens ; Binder, Christoph J; Stradal, Theresia E B; Rezaei, Nima ; Boztug, Kaan

The cytoskeletal regulator HEM1 governs B cell development and prevents autoimmunity Journal Article

Science Immunology, 5 (49), 2020, ISSN: 2470-9468.

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Guipouy, Delphine ; Gertner-Dardenne, Julie ; Pfajfer, Laurène ; German, Yolla ; Belmonte, Nathalie ; Dupré, Loïc

Granulysin- and granzyme-dependent elimination of myeloid cells by therapeutic ova-specific type 1 regulatory Ŧ cells Journal Article

International Immunology, 31 (4), pp. 239–250, 2019, ISSN: 1460-2377.

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Cheminant, Morgane ; Mahlaoui, Nizar ; Desconclois, Céline ; Canioni, Danielle ; Ysebaert, Loïc ; Dupré, Loïc ; Vasconcelos, Zilton ; Malphettes, Marion ; Moshous, Despina ; Neven, Bénédicte ; Rohrlich, Pierre-Simon ; Bernard, Marc ; Bertrand, Yves ; Fischer, Alain ; Suarez, Felipe

Lymphoproliferative disease in patients with Wiskott-Aldrich syndrome: Analysis of the French Registry of Primary Immunodeficiencies Journal Article

The Journal of Allergy and Clinical Immunology, 143 (6), pp. 2311–2315.e7, 2019, ISSN: 1097-6825.

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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.

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Sarkar, Koustav ; Han, Seong-Su ; Wen, Kuo-Kuang ; Ochs, Hans D; Dupré, Loïc ; Seidman, Michael M; Vyas, Yatin M

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

The Journal of Allergy and Clinical Immunology, 142 (1), pp. 219–234, 2018, ISSN: 1097-6825.

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Pfajfer, Laurène ; Mair, Nina K; Jiménez-Heredia, Raúl ; Genel, Ferah ; Gulez, Nesrin ; Ardeniz, Ömür; Hoeger, Birgit ; Bal, Sevgi Köstel ; Madritsch, Christoph ; Kalinichenko, Artem ; Chandra Ardy, Rico ; Gerçeker, Bengü ; Rey-Barroso, Javier ; Ijspeert, Hanna ; Tangye, Stuart G; Simonitsch-Klupp, Ingrid ; Huppa, Johannes B; van der Burg, Mirjam ; Dupré, Loïc ; Boztug, Kaan

Mutations affecting the actin regulator WD repeat-containing protein 1 lead to aberrant lymphoid immunity Journal Article

The Journal of Allergy and Clinical Immunology, 142 (5), pp. 1589–1604.e11, 2018, ISSN: 1097-6825.

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Brigida, Immacolata ; Zoccolillo, Matteo ; Cicalese, Maria Pia ; Pfajfer, Laurène ; Barzaghi, Federica ; Scala, Serena ; Oleaga-Quintas, Carmen ; Álvarez-Álvarez, Jesus A; Sereni, Lucia ; Giannelli, Stefania ; Sartirana, Claudia ; Dionisio, Francesca ; Pavesi, Luca ; Benavides-Nieto, Marta ; Basso-Ricci, Luca ; Capasso, Paola ; Mazzi, Benedetta ; Rosain, Jeremie ; Marcus, Nufar ; Lee, Yu Nee ; Somech, Raz ; Degano, Massimo ; Raiola, Giuseppe ; Caorsi, Roberta ; Picco, Paolo ; Moncada Velez, Marcela ; Khourieh, Joelle ; Arias, Andrés Augusto ; Bousfiha, Aziz ; Issekutz, Thomas ; Issekutz, Andrew ; Boisson, Bertrand ; Dobbs, Kerry ; Villa, Anna ; Lombardo, Angelo ; Neven, Benedicte ; Moshous, Despina ; Casanova, Jean-Laurent ; Franco, José Luis ; Notarangelo, Luigi D; Scielzo, Cristina ; Volpi, Stefano ; Dupré, Loïc ; Bustamante, Jacinta ; Gattorno, Marco ; Aiuti, Alessandro

T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency Journal Article

Blood, 132 (22), pp. 2362–2374, 2018, ISSN: 1528-0020.

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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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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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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).

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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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Université Toulouse Paul Sabatier

Université Toulouse Paul Sabatier

Région Occitanie

Région Occitanie

Fondation ARC

Fondation ARC

Seventh Framework Programme

Seventh Framework Programme