Inflammatory bowel diseases (IBDs) result from exacerbated immune activation in the intestinal mucosa. T cells participate to the immune homeostasis of the intestine but are also implicated in the inflammatory response during the disease. We study the repertoire of T cell receptors to identify, characterize and localize disease-associated T cell clones in the mucosa of IBD patients. In both healthy and inflammatory mucosa, T cells interact with numerous cellular partners, such as epithelial cells. To study this lympho-epithelial crosstalk in human, we culture organoid from normal or inflammatory tissues and analyze their interactions with autologous T cells isolated from the same organ. Our aim is to determine and modulate the pathways involved in these interactions in order to reduce tissular damage in the context of IBD.

CONTEXT: T lymphocytes are critical cellular actors in the host response to various pathogens i.e. viruses, bacteria and fungi and in the control of malignant cell transformation. Importantly, the thymus ensures a continuous production of naïve T cells with a diverse TCR repertoire capable to mount effective immune responses. However, this organ undergoes severe changes upon aging in its mass and architecture, accompanied by a progressive decrease in T cell production, a process referred to as “thymic involution”. Furthermore, the thymus is highly sensitive to myeloablative treatments used to cure hematological disorders such as genetic disorders or cancer by hematopoietic stem cell transplantation. Both aging and myeloablative treatments have deleterious effects on thymic epithelial cells, leading to a drastic reduction in T cell production and consequently to increased susceptibility to opportunistic infections, autoimmunity and cancer. Nevertheless, the thymus shows a high plasticity and is prone to regenerative therapies. Although in mice, certain growth factors or cytokines protect or regenerate thymic epithelial cells and improve thymopoiesis, their efficacy in humans in preclinical trials either failed or remains to be determined. Identifying effective therapeutic molecules to regenerate thymic functions thus still constitutes an unmet clinical need. In this context, we recently showed in mice that the administration of the epithelial growth and differentiation cytokine, RANK ligand (RANKL), ameliorates the regeneration of the thymus and T-cell reconstitution upon myeloablative treatments and bone marrow transplantation (BMT) (Lopes et al. EMBO Mol Med 2017 et brevet WO/2018/154122). OBJECTIVES: The objectives of this project are to determine: (1) whether T-cell production improved by RANKL enhances protection against lethal opportunistic infections in a pre-clinical BMT mouse model, (2) to what extent RANKL is beneficial to reverse age-related thymic involution, (3) the impact of RANKL on the prevention of bone loss by bisphosphonates upon BMT and thymic involution, (4) the translational potential of using RANKL to regenerate human thymic functions. In summary, the ambition of this project is to bring the proof of concept that RANKL could be clinically pertinent to improve the recovery of T-cell functions without inducing bone loss in pathophysiological conditions in which the thymus has been severely damaged. CONSORTIUM: This project is a close collaboration between three French research teams. It brings together a fully complementary expertise on the biology of thymic function in mice (Team #1) and humans (Team #2) as well as on bone physiology (Team #3). BIOMEDICAL RELEVANCE: This project is expected to improve the immune system by acting on the production of T lymphocytes by regenerating the thymic function. We are convinced that the expected results could have a significant impact on public health, given the incidence of 20 to 30% of mortality related to infections after HSC transplantation and the demographic increase in the number of elderly people in our societies, a phenomenon also associated with a high rate of infections. This project has the potential to improve the health of many patients who incur morbidity and mortality due to T cell deficiency and reduce the associated medical costs.

The Hu-Thy-L project aims to unravel how genetic variation impacts on chromatin accessibility, epigenetic modifications and/or transcription factors binding, leading to differences in thymocyte differentiation. The understanding of a “fine tuning” of thymopoiesis may improve our basic knowledge of human T cell development with a broad impact in the setting of immune responses and vaccines. It could also provide an insight into the mechanisms of oncogenic translocation in T acute lymphocytic leukemias. The thymus is the primary organ responsible for the generation of conventional T cells (aß T cells) as well as unconventional T cells including gd T cells and invariant NKT. In a population immunology approach, we characterized the variability of thymic function among 1,000 healthy adults of the Milieu Intérieur cohort. GWAS revealed an association between thymopoiesis and a common variant within the T-cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments in a region where TCR rearrangements start in early thymic progenitors. This region is also involved in TCRD-oncogene rearrangements that occur during early thymopoiesis. The aim of the Hu-Thy-L project is to unravel how this genetic variation could be associated with differences in chromatin accessibility, epigenetic changes and/or transcription factors binding, leading to differences in thymocyte differentiation. The understanding of a “fine tuning” of thymopoiesis may improve our basic knowledge of human T cell development with a broad impact in the setting of immune responses. It could also provide an insight into the mechanisms of oncogenic translocation involving the TCRD locus in T-ALL.