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 Dr. Paola Romagnoli, CNRS staff-scientist of our team, 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 and holder of an interface contract with the Inserm, characterises the epigenetic mechanisms controlling T cell fate and plasticity.
Patients that receive allografts require life-long immunosuppressive treatment to control the T lymphocytes that otherwise would reject the grafts. To reduce this treatment and its important secondary effects, the group led by Prof. Joost van Meerwijk, Professor at the Toulouse University and TMIT-teamleader, develops innovating therapies against graft rejection that are based on the administration of regulatory T lymphocytes.
PROJECT 1: 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.
PROJECT 2: We develop innovating therapies against graft-rejection
Regulatory T cells prevent bone-marrow allograft-rejection
We started our studies on the potential of regulatory T cells to prevent graft-rejection by assessing their capacity to favour acceptance of bone marrow grafts. We found that these cells act in a donor-specific manner to prevent rejection of bone marrow grafts.
A novel therapy against heart allograft rejection
Despite treatment with immunosuppressive drugs, heart allografts suffer from chronic rejection. We found that regulatory T cells of appropriate antigen-specificity can prevent chronic rejection of heart allografts in an experimental model. We obtained similar results with very immunogenic skin-allografts.
Regulatory T cell-therapy: a permanent solution?
In our bone marrow, skin, and heart allograft-models, we found that a single injection of regulatory T cells was sufficient to prevent rejection for prolonged periods. It appears that administered cells favoured the emergence of host regulatory T cells that prevent rejection. Thus, tolerance induced by these cells is “infectious” and should last a lifetime.
Regulatory T cells and prevention of chronic inflammation
Our team also works on a little-studied population of regulatory T cells (“CD8+CD28low”). We showed that these cells can prevent experimental colitis. We also demonstrated that the transcription factor AIRE, which allows the expression of tissue antigens in the thymus, is required for the development of the Treg that prevent colitis.
PROJECT 3 : 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.
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).
Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors Journal Article
Nature Immunol, 16 , pp. 628–634, 2015.
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.
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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.
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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.
Beta1 and Beta3 Integrins promote T Cell Receptor-mediated Cytotoxic T Lymphocyte Activation Journal Article
J. Biol. Chem., 278 (29), pp. 26983-91, 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.
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Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells Journal Article
Blood, 97 (5), pp. 1336-1342, 2001.
Interferon gamma gene polymorphism and susceptibility to, and severity of, rheumatoid arthritis Journal Article
The Lancet, 358 , pp. 2051-2052, 2001.
Pleiotropic effects of post-translational modifications on the fate of viral glycopeptides as cytotoxic T cell epitopes Journal Article
Journal of Biological Chemistry, 276 (41), pp. 38255-60, 2001.
Structural and functional identification of major histocompatibility complex class I-restricted self-peptides as naturally occurring molecular mimics of viral antigens. Possible role in CD8+ T cell-mediated, virus-induced autoimmune disease Journal Article
Journal of Biological Chemistry, 276 (22), pp. 19396-403, 2001.
Molecular and functional dissection of the H-2Db-restructed subdominant cytotoxic T cell response to lymphocytic choriomeningitis virus Journal Article
J. Virol., 75 , pp. in press, 2001.
CTL rapidly capture membrane fragments from target cells in a TCR signalling-dependent manner Journal Article
Journal of Immunology, 166 (6), pp. 3645-3649, 2001.
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.
Molecular determinants of T-cell immunity Journal Article
The immunologist, 8 (4 & 5), pp. 114-118, 2000.
Antigen recognition by CD8+ CTLs Book Chapter
Sitkovsky, M V; Henkart, P A (Ed.): Cytotoxic cells: basic mechanisms and medical applications, pp. 25-43, Lippincott Williams & Wilkins, Philadelphia, 2000.
Rheumatoid factor and antikeratin antibody are independent from presence of DR4 or DR1 in rheumatoid arthritis Journal Article
Rev Rhum Engl Ed, 66 (1), pp. 20-3, 1999.
Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis Journal Article
Arthritis Rheum, 42 (6), pp. 1093-100, 1999.
Genetically encoded and post-translationally modified forms of a major histocompatibility complex class I-restricted antigen bearing a glycosylation motif are independently processed and co-presented to cytotoxic T lymphocytes. Journal Article
J. Biol. Chem., 274 , pp. 36274-36280, 1999.
Protection from radiation-induced colitis requires MHC class II antigen expression by cells of hemopoietic origin Journal Article
Journal of Immunology, 163 (7), pp. 4033-40, 1999.
Virology, 256 (2), pp. 246-57, 1999.
Impaired T-cell fate specification in mice with an induced inactivation of Notch-1 Journal Article
Immunity, 10 , pp. 547-558, 1999.
Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients Journal Article
International Immunology, 11 (9), pp. 1411-22, 1999.
In vivo T lymphocyte tolerance in the absence of thymic clonal deletion mediated by haematopoietic cells Journal Article
Blood, 93 (11), pp. 3856-3862, 1999.
T cell receptor gene in synovial tissues of rheumatoid arthritis Journal Article
Int Rev Immunol, 17 (5-6), pp. 323-37, 1998.
Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis: evidence of increased interleukin-4 and interleukin-10 gene expression demonstrated in vitro by competitive reverse transcriptase-polymerase chain reaction Journal Article
Arthritis Rheum, 41 (1), pp. 48-57, 1998.
Peptide-major histocompatibility complex class I complex: from the structural and molecular basis to pharmacological principles and therapeutic applications Journal Article
Curr Top Microbiol Immunol, 232 , pp. 75-97, 1998.
J Immunol, 161 (2), pp. 553-62, 1998.
J Immunol, 161 (12), pp. 6939-46, 1998.
Substance P enhances cytokine-induced vascular cell adhesion molecule-1 (VCAM-1) expression on cultured rheumatoid fibroblast-like synoviocytes Journal Article
Clin Exp Immunol, 113 (2), pp. 269-75, 1998.
Tissue Antigens, 51 (1), pp. 10-9, 1998, ISSN: 0001-2815 (Print).
Thymic lineage commitment rather than selection causes genetic variations in size of CD4 and CD8 compartments Journal Article
J. Immunol., 160 (8), pp. 3649-54, 1998.
Homeostasis limits the development of mature CD8+ but not CD4+ thymocytes Journal Article
J. Immunol., 160 (6), pp. 2730-4, 1998.
Invariant chain regulation of MHC class II function in the secretory and endocytic pathways Journal Article
In: HLA and disease-The molecular basis, Svejgaard A. et al. (eds.), Alfred benzon Symposium, 40 , pp. 114-127, 1997.
Virology, 234 (1), pp. 62-73, 1997.
Role of CD8 in aberrant function of cytotoxic T lymphocytes Journal Article
J Exp Med, 186 (12), pp. 2033-8, 1997.
J Immunol, 158 (12), pp. 5757-64, 1997.
Dominant clones in immortalized T-cell lines from rheumatoid arthritis synovial membranes Journal Article
Tissue Antigens, 49 (5), pp. 431-7, 1997.
Quantitative impact of thymic clonal deletion on the T cell repertoire Journal Article
J. Exp. Med., 185 (3), pp. 377-83, 1997.
Related leucine-based cytoplasmic targeting signals in invariant chain and major histocompatibility complex class II molecules control endocytic presentation of distinct determinants in a single protein Journal Article
J Exp Med, 185 (3), pp. 429-38, 1997.
J Immunol, 156 (9), pp. 3480-5, 1996.
Processing and presentation of endocytically acquired protein antigens by MHC class II and class I molecules Journal Article
Immunol Rev, 151 , pp. 5-30, 1996.
Comparison of thymocyte development in normal and invariant chain- deficient mice provides evidence that maturation-related changes in TCR and co-receptor levels play a critical role in cell fate Journal Article
Int Immunol, 8 (9), pp. 1429-40, 1996.
Binding of viral antigens to major histocompatibility complex class I H- 2Db molecules is controlled by dominant negative elements at peptide non-anchor residues. Implications for peptide selection and presentation Journal Article
J Biol Chem, 271 (30), pp. 17829-36, 1996.
Evidence that binding site occupancy is necessary and sufficient for effective major histocompatibility complex (MHC) class II transport through the secretory pathway redefines the primary function of class II-associated invariant chain peptides (CLIP) Journal Article
J Exp Med, 184 (5), pp. 2061-6, 1996.
Optimal lymphocytic choriomeningitis virus sequences restricted by H- 2Db major histocompatibility complex class I molecules and presented to cytotoxic T lymphocytes Journal Article
J Virol, 69 (4), pp. 2297-305, 1995.
Relative implication of peptide residues in binding to major histocompatibility complex class I H-2Db: application to the design of high-affinity, allele-specific peptides Journal Article
Mol Immunol, 32 (12), pp. 895-907, 1995.
Discriminated selection among viral peptides with the appropriate anchor residues: implications for the size of the cytotoxic T- lymphocyte repertoire and control of viral infection Journal Article
J Virol, 69 (12), pp. 7423-9, 1995.
Inhibition of invariant chain (Ii)-calnexin interaction results in enhanced degradation of Ii but does not prevent the assembly of alpha beta Ii complexes Journal Article
J Exp Med, 182 (6), pp. 2027-36, 1995.
Genomics, 28 (2), pp. 241-50, 1995, ISSN: 0888-7543 (Print).
Evidence for lineage commitment and initiation of positive selection by thymocytes with intermediate surface phenotypes Journal Article
J. Immunol., 154 (12), pp. 6314-23, 1995.
Relative contribution of photo-addition, helper oligonucleotide and RNase H to the antisense effect of psoralen-oligonucleotide conjugates, on in vitro translation of Leishmania mRNAs Journal Article
Biochim Biophys Acta, 1219 (1), pp. 98-106, 1994.
Regulation of MHC class II intracellular transport and peptide loading Journal Article
In: Antigen processing and Presentation. R. E. Humphreys and S. K. Pierce (eds.), Academic Press Inc, pp. 109-123, 1994.
The CLIP region of invariant chain plays a critical role in regulating major histocompatibility complex class II folding, transport, and peptide occupancy Journal Article
J Exp Med, 180 (3), pp. 1107-13, 1994.
The different roles of MHC class recognition in thymocyte CD4 versus CD8 lineage commitment and positive selection Journal Article
Semin Immunol, 6 (4), pp. 231-9, 1994.
Defective major histocompatibility complex class II assembly, transport, peptide acquisition, and CD4+ T cell selection in mice lacking invariant chain expression Journal Article
J Exp Med, 177 (6), pp. 1699-712, 1993.
Relationship between invariant chain expression and major histocompatibility complex class II transport into early and late endocytic compartments Journal Article
J Exp Med, 177 (3), pp. 583-96, 1993.
Development of mature CD8+ thymocytes: selection rather than instruction? Journal Article
Science, 261 (5123), pp. 911-5, 1993.
Endogenous gene and amplifiable cDNA construct both produce unstable t- PA mRNA in Bowes melanoma cells Journal Article
J Biotechnol, 23 (2), pp. 143-51, 1992.
Gold-specific T cells in rheumatoid arthritis patients treated with gold Journal Article
J Clin Invest, 89 (1), pp. 254-8, 1992.
HLA polymorphism and T cell recognition of a conserved region of p190, a malaria vaccine candidate Journal Article
Int Immunol, 3 (9), pp. 899-906, 1991.
Selective interaction of Ni with an MHC-bound peptide Journal Article
Embo J, 10 (6), pp. 1303-6, 1991.
Selection of T cell epitopes and vaccine engineering Journal Article
Methods Enzymol, 203 , pp. 370-86, 1991.
Allelic exclusion of a T cell receptor-beta minilocus Journal Article
J Immunol, 147 (9), pp. 3224-8, 1991.
Allelic exclusion at DNA rearrangement level is required to prevent coexpression of two distinct T cell receptor beta genes Journal Article
J Exp Med, 174 (4), pp. 815-9, 1991.
Peptide-MHC interaction: a rational approach to vaccine design Journal Article
Int Rev Immunol, 6 (1), pp. 61-73, 1990.
Malaria antigens and MHC restriction Journal Article
Immunol Lett, 25 (1-3), pp. 265-70, 1990.
T-cell specific rearrangement of T-cell receptor beta transgenes in mice Journal Article
Embo J, 9 (4), pp. 1057-62, 1990.
Vaccine T-cell epitope selection by a peptide competition assay Journal Article
Proc Natl Acad Sci U S A, 86 (5), pp. 1629-33, 1989.
Peptide binding to MHC class II molecules: application to vaccine design Journal Article
In: Progress in Immunology, Melchers et al. (eds.), VII Springer-Verlag, pp. 1137-1143, 1989.
Use of immmunoadsorbent columns for antiAChR antibodies removal from plasma of myasthenia gravis patients Journal Article
Plsma Ther Transf Technol, 9 , pp. 73-76, 1988.
Anti AChR antibody: relevance to diagnosis and clinical aspects of myasthenia gravis Journal Article
Ital J Neurol Sci, 9 (2), pp. 141-5, 1988.
Bone modeling in gallium nitrate-treated rats Journal Article
Calcif Tissue Int, 40 (5), pp. 270-5, 1987, ISSN: 0171-967X (Print).
Mitochondrial calcium and bone mineralization in the rat fetus Journal Article
Bone Miner, 1 (2), pp. 157-66, 1986, ISSN: 0169-6009 (Print).
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J Gynecol Obstet Biol Reprod (Paris), 6 (5), pp. 625-31, 1977, ISSN: 0368-2315 (Print).
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.