Transcriptional Control of CD4⁺ T Cells Differentiation

Abstract

CD4⁺ T cells are essential orchestrators of immunity, giving rise to distinct effector and regulatory lineages. CD4⁺ T differentiation is tightly controlled by transcription factors and chromatin architecture, which together determine cell identity, functional capability, and adaptation to specific tissues. Although many lineage defining regulators have been identified, how three dimensional genome organization and context dependent transcriptional programs ultimately dictate T cell fate is still not completely understood. <br/> In this thesis, I investigated transcriptional and epigenetic mechanisms that drive T-cell differentiation and function, which resulted in three peer-reviewed publications. In the first study, I demonstrated that the chromatin organizer Satb1 is essential for stabilizing Th17 cell's identity by limiting IL-2/STAT5-driven reprogramming and enforcing Th17-specific gene networks. In the second study, I contributed to the identification of MEOX1 as a FOXP3-dependent transcription factor that strengthens human Treg identity and suppressive function by regulating key genes associated with the Treg program. In the third study, I supported the characterization of two functionally distinct Treg populations in visceral adipose tissue in a mouse model, revealing specialized transcriptional and metabolic programs that cooperate to maintain tissue and systemic metabolic homeostasis. And in the last study, currently published as a pre-print, I demonstrated that precise regulation of the chromatin remodeler Satb1 is essential for immune homeostasis: enforced Satb1 expression triggers lymphoproliferation, expands T and B cell compartments in secondary lymphoid organs, and skews CD4⁺ T cells toward a Tfh phenotype with enlarged germinal centers, increased non class switched GC B cells, and heightened auto antibody production. These results highlight the role of Satb1 in fine tuning CD4⁺ T cell and B cell responses and implicate its dysregulation as a contributor to autoimmune pathologies such as systemic lupus erythematosus. <br/> Together, these findings highlight the importance of chromatin structure, transcriptional networks, and tissue context in shaping T cell fate and function. They deepen our understanding of how transcriptional regulation and genome organization coordinate immune tolerance and effector responses, with implications for autoimmune disease, inflammation, and metabolic regulation.