Cathepsin L-dependent positive selection shapes clonal composition and functional fitness of CD4+ T cells
Year: 2025
Type: article
Abstract: 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.
Source: Nature Immunology
Authors: 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
Institutions: Institut für Immunologie, Ludwig-Maximilians-Universität München, Medizinische Hochschule Hannover, Technical University of Munich, University Medical Center Hamburg-Eppendorf, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, ETH Zurich, Institute of Molecular Health Sciences, University of Freiburg, Queensland University of Technology
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Memorial Sloan-Kettering Cancer Center, University of Minnesota, European Commission, Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, Queensland University of Technology, Ludwig-Maximilians-Universität München, Medical Research Council, National Health and Medical Research Council
Awards: G2234928323, European Network linking informatics and genomics of helper T cells, G306507530, G3133373473, G434337789, Delineating cortical and medullary self-tolerance mechanisms in the thymus, International Network of Excellence in Science Technology, Auswirkung mitochondrialer Signal und Stoffwechselwege auf die durch Dendritische Zellen vermittelte adaptive Immunantwort, TRR 355: Heterogenität und funktionelle Spezialisierung regulatorischer TZellen in unterschiedlichen Mikromilieus, Die Rolle von Cathepsin L für die Selektion eines funktionellen CD4 T Zell Repertoires, GRK 2606: Entschlüsselung zellulärer Proteasefunktionen durch Identifizierung und Analyse von Proteasesubstraten (ProtPath)
OpenAlex ID: W4411255279