Cathepsin L-dependent positive selection shapes clonal composition and functional fitness of CD4+ T cells

Elisabetta Petrozziello, Amina Sayed, João A. Freitas, Christine Federle, Jelena Nedjic, Sarina Ravens, Batuhan Akçabozan, Anna M. Schulz, Dietmar Zehn, Marc Schmidt-Supprian, Reinhard Obst, Immo Prinz, Martijn Verdoes, Jan Kisielow, Thomas Reinheckel, Tobias Straub, Stephen R. Daley & Ludger Klein (2025 June 13) Cathepsin L-dependent positive selection shapes clonal composition and functional fitness of CD4+ T cells. Nature Immunology volume 26, pages 1127–1138 (2025). Doi: https://doi.org/10.1038/s41590-025-02182-y

Abstract cited directly from the article: 

The physiological significance of thymic positive selection and its reliance on a single stromal cell type, cortical thymic epithelial cells, remain incompletely understood. The lysosomal cysteine protease cathepsin L (CTSL) has been implicated in generating major histocompatibility complex class II-bound peptides in cortical thymic epithelial cells for efficient CD4+ T cell differentiation. Here, we addressed the extent and nature of the CD4+ T cell repertoire changes associated with CTSL deficiency. In the absence of CTSL, a highly selective loss of T cell receptors resulted in a markedly reduced repertoire diversity. However, a similarly large proportion of nominally ‘CTSL-independent’ T cell receptors were retained. Clones representative of the second category experienced weaker positive selection signals in the absence of CTSL, which were sufficient for further maturation yet imprinted aberrant responsiveness to agonist stimulation and impaired homeostatic behavior. Together, these findings demonstrate that CTSL is crucial for both shaping full repertoire diversity and optimizing CD4+ T cell functionality.