Integrative T cell Immunobiology
Coordinators : J. van Meerwijk and O. Joffre
Our team uses an integrative biology approach to decipher the mechanisms that control, in a cell-autonomous or non-autonomous manner, intrathymic and peripheral differentiation of CD4 T cells.
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, studies development of regulatory T cells, key-players of immune-tolerance, in the thymus.
Depending on the nature and strength of the signals delivered by the antigen-presenting cells and the surrounding tissues, T lymphocytes mobilize different networks of transcription factors to induce distinct developmental programs that coordinate the acquisition of lineage-specific and danger-adapted phenotypes and functions. This differentiation is controlled and stabilised by epigenetic mechanisms. The group led by Dr. Olivier Joffre, associate professor at the Toulouse University, characterises the mechanisms controlling T cell fate and plasticity at the level of the chromatin.
Foxp3 regulatory T cells play a major role in the control chronic inflammatory diseases and auto-immune diseases and they inhibit anti-tumor immunity. The group led by Dr. Benoit Salomon, research director at Inserm who joined the team in 2022, studies the biology of regulatory T cells in peripheral tissues at homeostasis and in contexts of auto-immune diseases and cancers.
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.
We study the biology of regulatory T cells in order to develop new immunotherapies
The projects of the group led by Dr. Benoit Salomon aim to better understand the biology of Foxp3 regulatory T cells (Tregs) in homeostasis and the mechanisms involving Tregs in the control of autoimmune diseases and anti-tumor responses. These projects are organized around 4 axes. 1- Study of the biology and function of “ex-Tregs”, a population of conventional T lymphocytes which have been Tregs at some time in their life and have lost this status. 2- Study of the metabolic adaptation of Tregs in non-lymphoid tissues. 3- Study of the mechanisms of Treg mediated suppression in autoimmune diseases and cancers involving molecules of the TNF family. 4- Study of new therapeutic approaches to these diseases involving Tregs.
Most of these projects are carried out using genetically modified mice in which the expression of a gene of interest is eliminated specifically in Tregs. We thus generated conditional KO mice for receptors of the TNF family (TNFR2, 4-1BB), co-stimulatory molecules (ICOS) or molecules regulating cell metabolism (AMPK, LKB1). As a reference model of autoimmune diseases, we use experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. These projects notably require the use of multiparametric flow cytometry and transcriptomics technology.
In: Nephrol Dial Transplant, 2023, ISSN: 1460-2385.
TCR-independent CD137 (4-1BB) signaling promotes CD8+-exhausted T cell proliferation and terminal differentiation Journal Article
In: Immunity, vol. 56, pp. 1-18, 2023.
In: Frontiers in Immunology, 2022.
In: Diabetes, vol. 70, no. 8, pp. 1729-1737, 2021, ISSN: 1939-327X.
In: European Journal of Immunology, 2021, ISSN: 15214141.
In: Cell Reports, vol. 32, no. 7, 2020, ISSN: 22111247.
Endogenous retroviruses: Friend or foe of the immune system? Journal Article
In: Médecine/Sciences, vol. 36, no. 3, pp. 253-260, 2020, ISSN: 19585381.
In: Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 51, pp. 25839–25849, 2019, ISSN: 10916490.
In: Immunity, vol. 50, pp. 629–644, 2019.
In: Immunol Lett, vol. 204, pp. 9-15, 2018, ISSN: 0165-2478.
In: Front Immunol, vol. 9, pp. 2555, 2018, ISSN: 1664-3224.
In: Protein Cell, 2017, ISSN: 1674-800x.
In: Gerontology, 2017, ISSN: 0304-324x.
CD28neg and CD28low CD8+ regulatory T cells: Of Mice and Men Journal Article
In: Frontiers in immunology, vol. doi: 10.3389/fimmu.2017.00031, 2017.
In: Nat Immunol, vol. 17, no. 2, pp. 140-9, 2016, ISSN: 1529-2908.
In: Immunology, vol. 148, no. 2, pp. 187-96, 2016, ISSN: 1365-2567 (Electronic) 0019-2805 (Linking).
In: Oncotarget, 2016, ISSN: 19492553.
In: Nature Immunol, vol. 16, pp. 628–634, 2015.
In: Molecular Systems Biology, vol. 10, no. 10, pp. 754, 2014.
In: Epigenetics, vol. 9, no. 9, pp. 1238–1251, 2014.
In: Blood, vol. 121, no. 21, pp. 4303-10, 2013, ISSN: 1528-0020 (Electronic) 0006-4971 (Linking).
In: Eur J Immunol, vol. 43, no. 5, pp. 1356-62, 2013, ISSN: 1521-4141 (Electronic) 0014-2980 (Linking).
In: Journal of Immunology, vol. 189, no. 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
In: Kassiotis, G.; Liston, A. (Ed.): Regulatory T-Cells: Methods and Protocols, vol. 707, pp. 187-196, Springer, 2011.
In: Frontiers in Immunology, vol. 2, 2011, ISSN: 1664-3224.
AIRE-deficient CD8+CD28low regulatory T lymphocytes fail to control experimental colitis Journal Article
In: Proceedings of the National Academy of Sciences of the U.S.A., vol. 108, no. 30, pp. 12437-12442, 2011.
Thymic selection and lineage commitment of CD4+Foxp3+ regulatory T lymphocytes Journal Article
In: Prog Mol Biol Transl Sci., vol. 92, pp. 251-77, 2010.
Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes Journal Article
In: Nature Medicine, vol. 14, no. 1, pp. 88-92, 2008.
In: Med Sci (Paris), vol. 24, no. 8-9, pp. 689-691, 2008, ISSN: 0767-0974 (Print).
Murine CD8(+) regulatory T lymphocytes: The new era Journal Article
In: Hum Immunol, vol. 69, pp. 708-714, 2008, ISSN: 0198-8859 (Print).
In: Jiang, S. (Ed.): Regulatory T cells and clinical application, vol. 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
In: J. Immunol., vol. 179, pp. 6741-6748, 2007.
CD4+CD25+ regulatory T lymphocytes in bone marrow transplantation Journal Article
In: Seminars in Immunology, vol. 18, no. 2, pp. 128-135, 2006.
In: Gastroenterology, vol. 131, no. 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
In: J. Immunol., vol. 177, no. 2, pp. 1101-1107, 2006.
In: Int Immunol, vol. 18, no. 11, pp. 1509-1519, 2006.
Molecular signature of recent thymic selection events on effector and regulatory CD4+ T lymphocytes Journal Article
In: Journal of Immunology, vol. 175, pp. 5751-5758, 2005.
Genetic control of thymic development of CD4+CD25+FoxP3+ regulatory T lymphocytes Journal Article
In: Eur J Immunol, vol. 35, pp. 3525-3532, 2005.
In: J Immunol, vol. 173, no. 8, pp. 4799-805, 2004.
In: Blood, vol. 103, no. 11, pp. 4216-4221, 2004.
In: Eur J Immunol, vol. 33, no. 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
In: Eur J Immunol, vol. 33, no. 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
In: Immunology, vol. 108, pp. 24-31, 2003.
In: Journal of Biological Chemistry, vol. 277, pp. 19585-19593, 2002.
In: J Rheumatol, vol. 29, no. 1, pp. 15-20, 2002.
In: Arthritis Rheum, vol. 46, no. 7, pp. 1754-62, 2002.
In: Journal of Immunology, vol. 168, pp. 1644-1648, 2002.
A potential role for tyrosine kinase p56lck in rheumatoid arthritis synovial fluid T lymphocyte hyporesponsiveness Journal Article
In: International Immunology, vol. 13, no. 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.