Lymphotoxin limits Foxp3 + regulatory T cell development from Foxp3 lo precursors via IL-4 signaling.

Autor: Borelli A; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Santamaria JC; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Zamit C; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Apert C; Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291-CNRS UMR5051-University Toulouse III, Toulouse, France.; Microenvironment & Immunity Unit, Institut Pasteur, Paris, France., Chevallier J; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Pierre P; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Argüello RJ; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Spinelli L; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France., Irla M; Aix-Marseille University, CNRS, INSERM, CIML, Centre d'Immunologie de Marseille-Luminy, Turing Centre for Living Systems, Marseille, France. Magali.Irla@inserm.fr.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 14; Vol. 15 (1), pp. 6976. Date of Electronic Publication: 2024 Aug 14.
DOI: 10.1038/s41467-024-51164-5
Abstrakt: Regulatory T cells (T reg ) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25 + Foxp3 - and CD25 - Foxp3 lo precursors. However, the mechanisms regulating the recently identified Foxp3 lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α 1 β 2 (LTα 1 β 2 ) heterocomplex is upregulated during T reg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of T reg from Foxp3 lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα 1 β 2 -lymphotoxin β receptor-mediated interactions with mTEC limit T reg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic T reg development that fine-tunes the Foxp3 lo T reg precursor pathway by limiting IL-4 availability.
(© 2024. The Author(s).)
Databáze: MEDLINE
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