T cell-mediated Immune-Tolerance
Coordinator : J. van Meerwijk
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.
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.
Cell Reports, 32 (7), 2020, ISSN: 22111247.
Cell Reports, 32 (7), 2020, ISSN: 22111247.
Endogenous retroviruses: Friend or foe of the immune system? Journal Article
Médecine/Sciences, 36 (3), pp. 253-260, 2020, ISSN: 19585381.
European Journal of Immunology, 2020, ISSN: 15214141.
Proceedings of the National Academy of Sciences of the United States of America, 116 (51), pp. 25839–25849, 2019, ISSN: 10916490.
Immunity, 50 , pp. 629–644, 2019.
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.
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.
IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes Journal Article
Protein Cell, 2017, ISSN: 1674-800x.
Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review Journal Article
Gerontology, 2017, ISSN: 0304-324x.
CD28neg and CD28low CD8+ regulatory T cells: Of Mice and Men Journal Article
Frontiers in immunology, doi: 10.3389/fimmu.2017.00031 , 2017.
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.
Immunology, 148 (2), pp. 187-96, 2016, ISSN: 1365-2567 (Electronic) 0019-2805 (Linking).
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.
Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors Journal Article
Nature Immunol, 16 , pp. 628–634, 2015.
Molecular Systems Biology, 10 (10), pp. 754, 2014.
Epigenetics, 9 (9), pp. 1238–1251, 2014.
Blood, 121 (21), pp. 4303-10, 2013, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).
Eur J Immunol, 43 (5), pp. 1356-62, 2013, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).
Journal of Immunology, 189 (8), pp. 3831-7, 2012, ISSN: 1550-6606 (Electronic) 0022-1767 (Linking).
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.
Frontiers in Immunology, 2 , 2011, ISSN: 1664-3224.
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.
Thymic selection and lineage commitment of CD4+Foxp3+ regulatory T lymphocytes Journal Article
Prog Mol Biol Transl Sci., 92 , pp. 251-77, 2010.
Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes Journal Article
Nature Medicine, 14 (1), pp. 88-92, 2008.
Med Sci (Paris), 24 (8-9), pp. 689-691, 2008, ISSN: 0767-0974 (Print).
Murine CD8(+) regulatory T lymphocytes: The new era Journal Article
Hum Immunol, 69 , pp. 708-714, 2008, ISSN: 0198-8859 (Print).
Jiang, S (Ed.): Regulatory T cells and clinical application, in press , Springer, 2008, ISBN: 978-0-387-77908-9.
Shaping of the autoreactive regulatory T cell repertoire by thymic cortical positive selection Journal Article
J. Immunol., 179 , pp. 6741-6748, 2007.
CD4+CD25+ regulatory T lymphocytes in bone marrow transplantation Journal Article
Seminars in Immunology, 18 (2), pp. 128-135, 2006.
Gastroenterology, 131 (6), pp. 1775-85, 2006.
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.
Int Immunol, 18 (11), pp. 1509-1519, 2006.
Molecular signature of recent thymic selection events on effector and regulatory CD4+ T lymphocytes Journal Article
Journal of Immunology, 175 , pp. 5751-5758, 2005.
Genetic control of thymic development of CD4+CD25+FoxP3+ regulatory T lymphocytes Journal Article
Eur J Immunol, 35 , pp. 3525-3532, 2005.
J Immunol, 173 (8), pp. 4799-805, 2004.
Blood, 103 (11), pp. 4216-4221, 2004.
Eur J Immunol, 33 (6), pp. 1471-7, 2003.
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.
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.
Journal of Biological Chemistry, 277 , pp. 19585-19593, 2002.
J Rheumatol, 29 (1), pp. 15-20, 2002.
Arthritis Rheum, 46 (7), pp. 1754-62, 2002.
Journal of Immunology, 168 , pp. 1644-1648, 2002.
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.
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.