Message of the margins How RNA-binding proteins and mTOR signaling program human T cells

Message of the Margins: How RNA-binding proteins and mTOR signaling program human T cells explores how human T cells control protein production during immune activation. T cells are central to adaptive immunity and must remain quiescent under steady-state conditions while retaining the capacity to respond rapidly and precisely to infection or malignancy. Understanding how these cells achieve such flexibility requires insight not only into transcription, but also into the mechanisms that determine how messenger RNAs are processed, controlled, translated, and ultimately converted into functional proteins.
The work presented in this thesis examines how untranslated regions within mRNAs, RNA-binding proteins (RBPs), and upstream signaling pathways collectively shape protein expression in human T cells. It shows that quiescent T cells maintain a poised state through selective post-transcriptional regulation. In addition, it demonstrates that sequence features within mRNA can be used to predict protein abundance, leading to the development of SONAR, a machine-learning framework that identifies sequence determinants of protein expression across immune cell states.
The thesis further identifies the RNA-binding protein ZFP36L1 as a central hub in post-transcriptional regulatory networks and maps its dynamic interaction landscape during T cell activation. It also establishes mTOR as a key regulator of early proteome remodeling and T cell state transitions. Finally, the work reveals that mTOR controls cytokine production not only through canonical translational pathways, but also through 3′UTR-mediated mechanisms involving AU-rich elements and the RNA-binding protein DDX21. Together, these findings position post-transcriptional regulation as a fundamental determinant of human T cell function and provide new insight into how immune responses are programmed at the molecular level.