We recently demonstrated that the transcription factor Eomes is a key regulator of CD4+ T cell metabolic adaptation and epigenetic remodeling (Joulia et al, JEM, 2024). Furthermore, we recently identified a subset of Tregs co-expressing Foxp3 and Eomes that accumulate in inflamed tissues. These cells exhibit metabolic alterations, a loss of Treg identity and suppressive function, and increased plasticity (Peroceschi et al., under preparation).

We will combine animal models and patient cohorts to evaluate the contribution of Eomes+ Tregs in chronic inflammatory diseases and aging (HEC contribution). Eomes’ molecular mode of action in Tregs will be evaluated through metabolomic, transcriptomic, and epigenetic studies (VA contribution). In preclinical cancer models, we showed that Eomes controls the differentiation of the exhausted CD4+ T cell (T_EX) lineage and identified their progenitors (CD4+ T_PEX), a subset that exhibited self-renewal capacity and direct anti-tumoral activity (A. Agesta et al., Immunity, under review). Our ongoing project aims to decipher Eomes’ role in T_PEX and T_EX subset generation, maintenance and function, and to determine whether it affects the response to immunotherapy. We will explore whether Eomes modifies the metabolic dependency of T cells and examine its consequences on transcriptomic and epigenetic regulation . The clinical relevance of our findings will be evaluated in metastatic melanoma patients treated with immunotherapy.

                                                                                                                                                                                Coordinators: Anne S. Dejean

We recently demonstrated that epigenetic mechanisms, including chromatin modifiers (Adoue et al., 2019) and long non-coding RNAs (lncRNA) (Adoue et al. under preparation), play a crucial role in regulating CD4+ T cell gene expression programs. Moreover, our preliminary data, supported by emerging evidence from the literature, suggest that epitranscriptomic modifications add an additional layer of complexity to the differentiation and function of CD4+ T cells.

1) The function of most RNA-modifying enzymes in the differentiation and function of CD4+ T cells remains largely unknown. Our project aims to identify novel epitranscriptomic enzymes through in vitro CRISPR/Cas9 screening, elucidate their molecular mechanisms of action (notably using native RNA sequencing), and explore the interactions between epitranscriptomics and epigenetics. We have identified an RNA-modifying enzyme as a key regulator of the Th17/Treg balance, potentially through metabolic remodeling. Since its gene is located within a susceptibility locus for multiple sclerosis (MS), we will assess the consequences of its deletion in vivo using the EAE model and validate its function and role in CD4+ T cell metabolism in patients with MS.

2) Investigation of the role of the Long Non-Coding RNA Lcincr in CD4+ T Cell Subpopulations. Through deep RNA-seq and refined bioinformatic analysis, we identified > 2000 novel lncRNA genes in CD4+ T subsets. Among them, we identified Lcincr as a key regulator of Treg function and Th2 cell differentiation. We will explore pathways impacted by its deletion by transcriptomic assays. As GWAS studies linked Lcincr locus to severe asthma and inflammatory bowel diseases, the function of Lcincr in CD4+ T cells will be dissected in vivo using models of asthma and IBD and confirmed in human cohorts. 

Coordinator: Dr Veronique Adoue

Controlled T cell immunity is a prerequisite for health. An unbalanced response may lead to autoimmune diseases if the immune system reacts too strongly, or allow tumor expansion due to inadequate immune response. Hence, the control mechanisms for accurate T cell activation and differentiation are essential to maintain a good immune homeostasis. Signaling after the engagement of receptors expressed by T cells play an important role in controlling T cell functions and polymorphism or deficiency for these signaling genes could predispose to immune-mediated diseases.

We recently found that persistent HEV infection in elderly kidney transplant patients is associated with an accumulation of terminally differentiated T cells at the acute infection phase, with these cells displaying impaired mitochondrial function and features of senescence (Gouilly et al., under preparation). Upcoming research will explore the mechanisms driving T cell senescence, focusing on the link between metabolic dysfunction and epigenetic reprogramming. By combining cellular, molecular and metabolomics approaches, we will compare immune responses across acute and chronic infection stages and evaluate whether metabolic reprogramming can restore T cell function, supporting the development of targeted therapeutic strategies for chronic infection. Furthermore, by profiling the energy metabolism of immune cells from elderly participants (INSPIRE-T cohort), we recently identified a correlation between mitochondrial dependency and IF1 expression in CD4 T cells, and improvement of functional capacity in the elderly (Jabrane-Ferrat et al., in revision, Patent #EP24315476). Using CD4-specific IF1 deficient mice and CRISPR/Cas9 edited human T cells, we will decipher the mechanisms underlying these correlations by unveiling the role of IF1 in CD4+ T cell differentiation, metabolic adaptation and function across tissues and aging. We will also examine whether targeting the IF1 pathway is an effective strategy for promoting healthy aging in mice and assess the potential of IF1 levels as a biomarker for monitoring age-related decline in the INSPIRE-T cohort.

Coordinators: Dr Hicham El Costa