Die Rolle von Cathepsin L für die Selektion eines funktionellen CD4 T Zell Repertoires
Zusammenfassung der Projektergebnisse
The physiological significance of thymic positive selection and its reliance on a single stromal cell type, cortical thymic epithelial cells (cTECs), remain incompletely understood. Cathepsin L (Ctsl) has been implicated in generating MHCII-bound peptides in cTECs for efficient CD4 T cell differentiation. Here, we addressed the extent and nature of CD4 repertoire changes associated with Ctsl-deficiency. In the absence of Ctsl, a highly selective loss of TCRs promotes a drastic reduction in repertoire diversity. However, a similarly large proportion of nominally ‘Ctsl-independent’ TCRs are retained. We demonstrate that clones representative of the second category experience weaker positively selecting signals in the absence of Ctsl, which are sufficient for further maturation, yet imprint aberrant responsiveness to agonist stimulation and impaired homeostatic behavior. Hence, Ctsl is not only crucial for full repertoire diversity but also optimizes CD4 T cell functionality.
Projektbezogene Publikationen (Auswahl)
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Antigen presentation for central tolerance induction. Nature Reviews Immunology, 25(1), 57-72.
Klein, Ludger & Petrozziello, Elisabetta
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Cathepsin L-dependent positive selection shapes clonal composition and functional fitness of CD4+ T cells. Nature Immunology, 26(7), 1127-1138.
Petrozziello, Elisabetta; Sayed, Amina; Freitas, João A.; Federle, Christine; Nedjic, Jelena; Ravens, Sarina; Akçabozan, Batuhan; Schulz, Anna M.; Zehn, Dietmar; Schmidt-Supprian, Marc; Obst, Reinhard; Prinz, Immo; Verdoes, Martijn; Kisielow, Jan; Reinheckel, Thomas; Straub, Tobias; Daley, Stephen R. & Klein, Ludger
