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

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

  • Nat Immunol. 2025 Jul;26(7):1127-1138. doi: 10.1038/s41590-025-02182-y.
Elisabetta Petrozziello 1,  Amina Sayed 1,  João A Freitas 1,  Christine Federle 1,  Jelena Nedjic 1,  Sarina Ravens 2,  Batuhan Akçabozan 1,  Anna M Schulz 3 4,  Dietmar Zehn 3,  Marc Schmidt-Supprian 5,  Reinhard Obst 1,  Immo Prinz 2 6,  Martijn Verdoes 7,  Jan Kisielow 8 9,  Thomas Reinheckel 10,  Tobias Straub 11,  Stephen R Daley # 12,  Ludger Klein # 13
Affiliations

Affiliations

  • 1 Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany.
  • 2 Institute of Immunology, Hannover Medical School, Hannover, Germany.
  • 3 Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan and TUM Center for Infection Prevention, Technical University of Munich, Freising, Germany.
  • 4 Onkologisches Zentrum Freising MVZ, Freising, Germany.
  • 5 Institute for Experimental Hematology, Center for Translational Cancer Research (TranslaTUM), School of Medicine and Health, Technical University of Munich, Munich, Germany.
  • 6 Institute of Systems Immunology, Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 7 Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  • 8 Institute for Molecular Health Sciences, ETH Zürich, Zürich, Switzerland.
  • 9 Repertoire Immune Medicines, Schlieren, Switzerland.
  • 10 Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 11 Bioinformatics Unit, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany.
  • 12 Centre for Immunology and Infection Control, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
  • 13 Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany. ludger.klein@med.uni-muenchen.de.
  • # Contributed equally.
PMID: 40514418 DOI: 10.1038/s41590-025-02182-y
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.

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