Cathepsin L-Dependent Positive Selection Shapes Clonal Composition and Functional Fitness of CD4 T Cells [RNA]

The physiological significance of thymic positive selection and its reliance on a single stromal cell type, cortical thymic epithelial cells (cTECs), remain poorly understood. Cathepsin L (Ctsl) has been implicated in generating MHCII-bound peptides in cTECs for efficient CD4 T cell differentiation. Here, we addressed whether Ctsl-deficiency impacts the CD4 compartment not only numerically, but also qualitatively. When Ctsl is absent, many TCRs disappear from the repertoire due to a genuine defect in positive selection, while some allegedly ‘Ctsl-independent’ TCRs are retained. We demonstrate that these clones experience weaker positively selecting signals in absence of Ctsl, which suffice for further maturation, yet imprint aberrant responsiveness to agonist stimulation and impaired homeostatic behavior. Hence, the Ctsl-generated peptidome in cTECs engenders TCR-pMHCII interactions at the upper end of the permissible affinity spectrum to optimize both CD4 T cell diversity and functionality.