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

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<sup>+</sup> T cell differentiation. Here, we addressed the extent and nature of the CD4<sup>+</sup> 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<sup>+</sup> T cell functionality.

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Publication Details

Journal
Nature Immunology
Published
2025-06-13
DOI
https://doi.org/10.1038/s41590-025-02182-y
Citations
4
Primary Topic
T-cell and B-cell Immunology
Type
article
Field-Weighted Citation Impact
3.19

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article

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

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4 citations
Nature Immunology
T-cell and B-cell Immunology
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article

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

Martijn Verdoes, Batuhan Akçabozan, Dietmar Zehn, Immo Prinz, Jan Kisielow, Sarina Ravens, Alaa Sayed, Jelena Nedjic, Christine Federle, Thomas Reinheckel, João Augusto Teixeira de Freitas, Tobias Straub, Stephen R. Daley, Ludger Klein, Reinhard Obst, Elisabetta Petrozziello, Marc Schmidt‐Supprian, Anna M. Schulz
article en
4 citations

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<sup>+</sup> T cell differentiation. Here, we addressed the extent and nature of the CD4<sup>+</sup> 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<sup>+</sup> T cell functionality.

Nature ImmunologyVol. 26(7)
Radboud University Nijmegen (NL), Universität Hamburg (DE), Queensland University of Technology (AU), University of Freiburg (DE), Radboud University Medical Center (NL), Medizinische Hochschule Hannover (DE), ETH Zurich (CH), Bavarian State Research Center for Agriculture (DE), University Medical Center Hamburg-Eppendorf (DE), Radboud Institute for Molecular Life Sciences (NL), Urologische Klinik München (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE)
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
Life in Land
Openalex Percentile: Top 8%
T-cell and B-cell Immunology
3.19
DOIOpen Access PDFOpenAlex
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