T cell-mediated Immune-Tolerance

Coordinator : J. van Meerwijk

Scientific objectives


T lymphocytes play a central role in the defence of the organism against pathogens and tumours. The mechanisms involved in the development of T cells in the thymus also cause the generation of autospecific and therefore potentially dangerous T cells. To avoid autoimmune pathology, immune-tolerance needs to be established. The group led by Prof. Joost van Meerwijk, Professor at the Toulouse University and TMIT-teamleader, studies development of regulatory T cells, key-players of immune-tolerance, in the thymus.

During immune-responses to pathogens and tumours, T lymphocytes differentiate into specialised effector subsets. This differentiation is induced by the microenvironment in which the T cell is activated and controlled and stabilised by epigenetic mechanisms. The group led by Dr. Olivier Joffre, associate professor at the Toulouse University, characterises the epigenetic mechanisms controlling T cell fate and plasticity.

Our Projects


We study how T cell mediated immune tolerance develops in the thymus
The regulatory T cell repertoire is autospecific

In accordance with one of their main functions, we were the first to demonstrate that the repertoire of regulatory T cells is enriched in autospecific cells. This allows these cells to be activated when and where also the very dangerous autospecific T cells that cause autoimmunity are activated.

How does the thymus limit development of regulatory T cells?

The number of regulatory T cells developing in the thymus is much lower than the number of precursors with appropriate antigen-specificity. This suggests that the thymus somehow limits differentiation of regulatory T cells. We showed that limiting the number of precursors does not increase the proportion of cells differentiating into the regulatory lineage, which suggests that precursors are involved in shaping the niche.

Paradoxically increased development of regulatory T cells in autoimmune-prone mice

Regulatory T cells protect us from autoimmune pathology. Our finding that in autoimmune-prone mice more of these cells develop was therefore very surprising. Data from our lab also showed genetic control of the development of regulatory T cells. One involved locus is closely linked to the major histocompatibility locus (MHC).

Regulatory T cells migrate back to the thymus

We demonstrated that regulatory T cells activated during immune-responses migrate back to the thymus and influence induction of immune-tolerance. We are currently working on further consequences

of this intriguing phenomenon.

We characterize the epigenetic mechanisms controlling T cell fate

The integrity of the organism is ensured by a tight interplay between conventional and regulatory T cells. The intercellular and environmental signals regulating their programming and crosstalk and the signalling events and transcriptional networks they induce have been extensively characterized. However, we now know that T cell identity is also largely controlled at the epigenetic level. The group led by Dr. Olivier Joffre, associate professor at the Toulouse University and holder of an interface contract with the Inserm, characterises the epigenetic mechanisms controlling T cell fate. It deciphers the role of non-coding RNAs and of several chromosomal proteins in the response of conventional and regulatory T cells to environmental signals and in the interplay between these two populations of cells.

 

 

Other information


Publications

2020

Maqbool, Muhammad Ahmad ; Pioger, Léo; El Aabidine, Amal Zine ; Karasu, Nezih ; Molitor, Anne Marie ; Dao, Lan T M; Charbonnier, Guillaume ; van Laethem, Francois ; Fenouil, Romain ; Koch, Frederic ; Lacaud, Georges ; Gut, Ivo ; Gut, Marta ; Amigorena, Sebastian ; Joffre, Olivier ; Sexton, Thomas ; Spicuglia, Salvatore ; Andrau, Jean Christophe

Alternative Enhancer Usage and Targeted Polycomb Marking Hallmark Promoter Choice during T Cell Differentiation Journal Article

Cell Reports, 32 (7), 2020, ISSN: 22111247.

Abstract | Links | BibTeX

Maqbool, Muhammad Ahmad ; Pioger, L{é}o; {El Aabidine}, Amal Zine ; Karasu, Nezih ; Molitor, Anne Marie ; Dao, Lan T M; Charbonnier, Guillaume ; van Laethem, Francois ; Fenouil, Romain ; Koch, Frederic ; Lacaud, Georges ; Gut, Ivo ; Gut, Marta ; Amigorena, Sebastian ; Joffre, Olivier ; Sexton, Thomas ; Spicuglia, Salvatore ; Andrau, Jean Christophe

Alternative Enhancer Usage and Targeted Polycomb Marking Hallmark Promoter Choice during T Cell Differentiation Journal Article

Cell Reports, 32 (7), 2020, ISSN: 22111247.

Abstract | Links | BibTeX

Adoue, Véronique ; Joffre, Olivier

Endogenous retroviruses: Friend or foe of the immune system? Journal Article

Médecine/Sciences, 36 (3), pp. 253-260, 2020, ISSN: 19585381.

Abstract | Links | BibTeX

Darrigues, Julie ; Santamaria, Jeremy C; Galindo-Albarrán, Ariel ; Robey, Ellen A; Joffre, Olivier P; van Meerwijk, Joost P M; Romagnoli, Paola

Robust intrathymic development of regulatory T cells in young NOD mice is rapidly restrained by recirculating cells Journal Article

European Journal of Immunology, 2020, ISSN: 15214141.

Abstract | Links | BibTeX

2019

Gehrmann, Ulf ; Burbage, Marianne ; Zueva, Elina ; Goudot, Christel ; Esnault, Cyril ; Ye, Mengliang ; Carpier, Jean Marie ; Burgdorf, Nina ; Hoyler, Thomas ; Suarez, Guadalupe ; Joannas, Leonel ; Heurtebise-Chrétien, Sandrine ; Durand, Sylvère ; Panes, Rébecca ; Bellemare-Pelletier, Angélique ; Sáez, Pablo J; Aprahamian, Fanny ; Lefevre, Deborah ; Adoue, Veronique ; El Aabidine, Amal Zine ; Ahmad, Maqbool Muhammad ; Hivroz, Claire ; Joffre, Olivier ; Cammas, Florence ; Kroemer, Guido ; Gagnon, Etienne ; Andrau, Jean Christophe ; Amigorena, Sebastian

Critical role for TRIM28 and HP1$beta$/$gamma$ in the epigenetic control of T cell metabolic reprograming and effector differentiation Journal Article

Proceedings of the National Academy of Sciences of the United States of America, 116 (51), pp. 25839–25849, 2019, ISSN: 10916490.

Abstract | Links | BibTeX

Adoue, V; Binet, B; Malbec, A; Fourquet, J; Romagnoli, P; van Meerwijk, J P M; Amigorena, S; Joffre, O P

The Histone Methyltransferase SETDB1 Controls T Helper Cell Lineage Integrity by Repressing Endogenous Retroviruses. Journal Article

Immunity, 50 , pp. 629–644, 2019.

Abstract | Links | BibTeX

2018

Santamaria, J; Darrigues, J; van Meerwijk, J P M; Romagnoli, P

Antigen-presenting cells and T-lymphocytes homing to the thymus shape T cell development Journal Article

Immunol Lett, 204 , pp. 9-15, 2018, ISSN: 0165-2478.

Links | BibTeX

Araujo Furlan, C L; Tosello Boari, J; Rodriguez, C; Canale, F P; Fiocca Vernengo, F; Boccardo, S; Beccaria, C G; Adoue, V; Joffre, O; Gruppi, A; Montes, C L; Acosta Rodriguez, E V

Limited Foxp3(+) Regulatory T Cells Response During Acute Trypanosoma cruzi Infection Is Required to Allow the Emergence of Robust Parasite-Specific CD8(+) T Cell Immunity Journal Article

Front Immunol, 9 , pp. 2555, 2018, ISSN: 1664-3224.

Links | BibTeX

2017

Apert, C; Romagnoli, P; van Meerwijk, J P M

IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes Journal Article

Protein Cell, 2017, ISSN: 1674-800x.

Links | BibTeX

Darrigues, J; van Meerwijk, J P M; Romagnoli, P

Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review Journal Article

Gerontology, 2017, ISSN: 0304-324x.

Links | BibTeX

Vuddamalay, Y; van Meerwijk, J P M

CD28neg and CD28low CD8+ regulatory T cells: Of Mice and Men Journal Article

Frontiers in immunology, doi: 10.3389/fimmu.2017.00031 , 2017.

BibTeX

2016

Decque, A *; Joffre, O *; Magalhaes, J G *; Cossec, J C *; Blecher-Gonen, R; Lapaquette, P; Silvin, A; Manel, N; Joubert, P E; Seeler, J S; Albert, M L; Amit, I; Amigorena, S; Dejean, A

Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing Journal Article

Nat Immunol, 17 (2), pp. 140-9, 2016, ISSN: 1529-2908.

Links | BibTeX

Vuddamalay, Y; Attia, M; Vicente, R; Pomie, C; Enault, G; Leobon, B; Joffre, O; Romagnoli, P; van Meerwijk, J P

Mouse and human CD8(+) CD28(low) regulatory T lymphocytes differentiate in the thymus Journal Article

Immunology, 148 (2), pp. 187-96, 2016, ISSN: 1365-2567 (Electronic) 0019-2805 (Linking).

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Hamdi, Y; Soucy, P; Adoue, V; Michailidou, K; Canisius, S; Lemaçon, A; Droit, A; Andrulis, I L; Anton-Culver, H; Arndt, V; Baynes, C; Blomqvist, C; Bogdanova, N V; Bojesen, S E; Bolla, M K; Bonanni, B; Borresen-Dale, AL ; Brand, J S; Brauch, H; Brenner, H; Broeks, A; Burwinkel, B; Chang-Claude, J; Couch, F J; Cox, A; Cross, S S; Czene, K; Darabi, H; Dennis, J; Devilee, Pr ; Dörk, T; Dos-Santos-Silva, I; Eriksson, M; Fasching, P A; Figueroa, J; Flyger, H; Garcia-Closas, M; Giles, G G; Goldberg, M S; Gonzalez-Neira, A; Grenaker-Alnaes, G; Guénel, P; Haeberle, L; Haiman, C A; Hamann, U; Hallberg, E; Hooning, M J; Hopper, J L; Jakubowska, A; Jones, M; Kabisch, M; Kataja, V; Lambrechts, D; Le Marchand Land Lindblom, A; Lubinski Jand Mannermaa, A; Maranian, M; Margolin, S; Marme, F; Milne, R L; Neuhausen, S L; Nevanlinna, H; Neven, P; Olswold, C; Peto, J; Plaseska-Karanfilska, D; Pylkäs, K; Radice, P; Rudolph, A; Sawyer, E J; Schmidt, M K; Shu, X O; Southey, M C; Swerdlow, A; Tollenaar, R A E M; Tomlinson, I; Torres, D; Truong, T; Vachon, C; Van Den Ouweland, A M W; Wang, Q; Winqvist, R; Zheng, W; Benitez, J; Chenevix-Trench, G; Dunning, A M; Pharoah, P D P; Kristensen, V; Hall, P; Easton, D F; Pastinen, T; Nord, S; Simard, J

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21 Journal Article

Oncotarget, 2016, ISSN: 19492553.

Abstract | Links | BibTeX

2015

Thiault, N; Darrigues, J; Adoue, V; Gros, M; Binet, B; Perals, C; Leobon, B; Fazilleau, N; Joffre, O P; Robey, E A; van Meerwijk, J P M; Romagnoli, P

Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors Journal Article

Nature Immunol, 16 , pp. 628–634, 2015.

Links | BibTeX

2014

Adoue, V; Schiavi, A; Light, N; Almlof, J C; Lundmark, P; Ge, B; Kwan, T; Caron, M; Ronnblom, L; Wang, C; Chen, S H; Goodall, A H; Cambien, F; Deloukas, P; Ouwehand, W H; Syvanen, A C; Pastinen, T

Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs Journal Article

Molecular Systems Biology, 10 (10), pp. 754, 2014.

Abstract | Links | BibTeX

Light, N; Adoue, V; Ge, B; Chen, S-H; Kwan, T; Pastinen, T

Interrogation of allelic chromatin states in human cells by high-density ChIP-genotyping. Journal Article

Epigenetics, 9 (9), pp. 1238–1251, 2014.

Abstract | Links | BibTeX

2013

Pasquet, L; Douet, J Y; Sparwasser, T; Romagnoli, P; van Meerwijk, J P M

Long-term prevention of chronic allograft rejection by regulatory T-cell immunotherapy involves host Foxp3-expressing T cells Journal Article

Blood, 121 (21), pp. 4303-10, 2013, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).

Links | BibTeX

Tellier, J; Andrianjaka, A; Vicente, R; Thiault, N; Enault, G; Garchon, H J; van Meerwijk, J P M; Romagnoli, P

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility Journal Article

Eur J Immunol, 43 (5), pp. 1356-62, 2013, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).

Links | BibTeX

2012

Romagnoli, P; Dooley, J; Enault, G; Vicente, R; Malissen, B; Liston, A; van Meerwijk, J P M

The thymic niche does not limit development of the naturally diverse population of mouse regulatory T lymphocytes Journal Article

Journal of Immunology, 189 (8), pp. 3831-7, 2012, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).

Links | BibTeX

2011

Nouzé, C; Pasquet, L; van Meerwijk, J P M

In vitro expansion of alloantigen-specific regulatory T cells and their use in prevention of allograft-rejection Book Chapter

Kassiotis, G; Liston, A (Ed.): Regulatory T-Cells: Methods and Protocols, 707 , pp. 187-196, Springer, 2011.

BibTeX

Pasquet, Lise ; Joffre, Olivier ; Santolaria, Thibault ; van Meerwijk, Joost

Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells Journal Article

Frontiers in Immunology, 2 , 2011, ISSN: 1664-3224.

Links | BibTeX

Pomie, C; Vicente, R; Vuddamalay, Y; Ardesjö Lundgren, B; van der Hoek, M; Enault, G; Kagan, J; Fazilleau, N; Scott, H S; Romagnoli, P; van Meerwijk, J P M

AIRE-deficient CD8+CD28low regulatory T lymphocytes fail to control experimental colitis Journal Article

Proceedings of the National Academy of Sciences of the U.S.A., 108 (30), pp. 12437-12442, 2011.

BibTeX

2010

Romagnoli, P; van Meerwijk, J P M

Thymic selection and lineage commitment of CD4+Foxp3+ regulatory T lymphocytes Journal Article

Prog Mol Biol Transl Sci., 92 , pp. 251-77, 2010.

BibTeX

2008

Joffre, O; Santolaria, T; Calise, D; Al Saati, T; Hudrisier, D; Romagnoli, P; van Meerwijk, J P M

Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes Journal Article

Nature Medicine, 14 (1), pp. 88-92, 2008.

BibTeX

Joffre, O; Santolaria, T; van Meerwijk, J P M

[Tregs-based immunotherapy: an efficient way to fully inhibit acute and chronic rejection.] Journal Article

Med Sci (Paris), 24 (8-9), pp. 689-691, 2008, ISSN: 0767-0974 (Print).

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Pomie, C; Menager-Marcq, I; van Meerwijk, J P M

Murine CD8(+) regulatory T lymphocytes: The new era Journal Article

Hum Immunol, 69 , pp. 708-714, 2008, ISSN: 0198-8859 (Print).

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Romagnoli, P; Ribot, J; Tellier, J; van Meerwijk, J P M

Thymic and peripheral generation of CD4+Foxp3+ regulatory T cells Book Chapter

Jiang, S (Ed.): Regulatory T cells and clinical application, in press , Springer, 2008, ISBN: 978-0-387-77908-9.

Links | BibTeX

2007

Ribot, J; Enault, G; Pilipenko, S; Huchencq, A; Calise, M; Hudrisier, D; Romagnoli, P; van Meerwijk, J P M

Shaping of the autoreactive regulatory T cell repertoire by thymic cortical positive selection Journal Article

J. Immunol., 179 , pp. 6741-6748, 2007.

BibTeX

2006

Joffre, O; van Meerwijk, J P M

CD4+CD25+ regulatory T lymphocytes in bone marrow transplantation Journal Article

Seminars in Immunology, 18 (2), pp. 128-135, 2006.

BibTeX

Menager-Marcq, I; Pomie, C; Romagnoli, P; van Meerwijk, J P M

CD8+CD28- regulatory T lymphocytes prevent experimental inflammatory bowel disease in mice Journal Article

Gastroenterology, 131 (6), pp. 1775-85, 2006.

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Ribot, J; Romagnoli, P; van Meerwijk, J P M

Agonist ligands expressed by thymic epithelium enhance positive selection of regulatory T lymphocytes from precursors with a normally diverse TCR-repertoire Journal Article

J. Immunol., 177 (2), pp. 1101-1107, 2006.

BibTeX

Tellier, J; van Meerwijk, J P M; Romagnoli, P

An MHC-linked locus modulates thymic differentiation of CD4+CD25+Foxp3+ regulatory T lymphocytes Journal Article

Int Immunol, 18 (11), pp. 1509-1519, 2006.

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2005

Romagnoli, P; Hudrisier, D; van Meerwijk, J P M

Molecular signature of recent thymic selection events on effector and regulatory CD4+ T lymphocytes Journal Article

Journal of Immunology, 175 , pp. 5751-5758, 2005.

BibTeX

Romagnoli, P; Tellier, J; van Meerwijk, J P M

Genetic control of thymic development of CD4+CD25+FoxP3+ regulatory T lymphocytes Journal Article

Eur J Immunol, 35 , pp. 3525-3532, 2005.

BibTeX

2004

Cannarile, M A; Decanis, N; van Meerwijk, J P; Brocker, T

The role of dendritic cells in selection of classical and nonclassical CD8+ T cells in vivo Journal Article

J Immunol, 173 (8), pp. 4799-805, 2004.

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Joffre, O; Gorsse, N; Romagnoli, P; Hudrisier, D; van Meerwijk, J P M

Induction of antigen-specific tolerance to bone-marrow allografts with CD4+CD25+ T lymphocytes Journal Article

Blood, 103 (11), pp. 4216-4221, 2004.

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2003

Capone, M; Lees, R L; Finke, D; Ernst, B; van Meerwijk, J P M; MacDonald, H R

Selective absence of CD8+ TCRalpha beta+ intestinal epithelial cells in transgenic mice expressing beta2-microglobulin-associated ligands exclusively on thymic cortical epithelium. Journal Article

Eur J Immunol, 33 (6), pp. 1471-7, 2003.

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Cemerski, S; van Meerwijk, J P M; Romagnoli, P

Oxidative stress-induced T lymphocyte hyporesponsiveness is caused by structural modification rather than proteasomal degradation of crucial signaling molecules Journal Article

Eur J Immunol, 33 (8), pp. 2178-85, 2003.

BibTeX

Hudrisier, D; Feau, S; Bonnet, V; Romagnoli, P; van Meerwijk, J P M

In vivo maintenance of T lymphocyte unresponsiveness induced by thymic medullary epithelium requires antigen presentation by radioresistant cells Journal Article

Immunology, 108 , pp. 24-31, 2003.

BibTeX

2002

Cemerski, S; Cantagrel, A; van Meerwijk, J P M; Romagnoli, P

Reactive oxygen species differentially affect T cell receptor signaling pathways Journal Article

Journal of Biological Chemistry, 277 , pp. 19585-19593, 2002.

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Constantin, A; Lauwers-Cances, V; Navaux, F; Abbal, M; van Meerwijk, J; Mazieres, B; Cambon-Thomsen, A; Cantagrel, A

Collagenase-1 (MMP-1) and HLA-DRB1 gene polymorphisms in rheumatoid arthritis: a prospective longitudinal study Journal Article

J Rheumatol, 29 (1), pp. 15-20, 2002.

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Constantin, A; Lauwers-Cances, V; Navaux, F; Abbal, M; van Meerwijk, J; Mazieres, B; Cambon-Thomsen, A; Cantagrel, A

Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study Journal Article

Arthritis Rheum, 46 (7), pp. 1754-62, 2002.

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Romagnoli, P; Hudrisier, D; van Meerwijk, J P M

Preferential recognition of self-antigens despite normal thymic deletion of CD4+CD25+ regulatory T cells Journal Article

Journal of Immunology, 168 , pp. 1644-1648, 2002.

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2001

Romagnoli, P; Strahan, D; Pelosi, M; Cantagrel, A; van Meerwijk, J P M

A potential role for tyrosine kinase p56lck in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness Journal Article

International Immunology, 13 (3), pp. 305-312, 2001.

BibTeX

Impact on the society

A better understanding of the development of T lymphocytes and their differentiation upon aggression by pathogens or tumours will lead to development of more specific and effective innovating therapies against e.g. immunopathologies. The regulatory T cell-based therapy against allograft-rejection developed by our team is an excellent example.

The TMIT team is also much involved in immunology-teaching at the Toulouse University. Its members teach courses at distinct academic levels, direct the Master program in Immunology and Infectious Diseases, and train PhD-students.

Agence nationale de la recherche

Agence nationale de la recherche

Fondation de recherche médicale

Fondation de recherche médicale

Région Occitanie

Région Occitanie

Fondation ARC

Fondation ARC

Ligue contre le cancer

Ligue contre le cancer

INSERM

INSERM

UT3

UT3

CNRS

CNRS

Sanofi Genzyme

Sanofi Genzyme