Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation
A better understanding of the mechanisms regulating CD8+ T cell differentiation is essential to develop new strategies to fight infections and cancer. Using genetic mouse models and blocking antibodies, we uncovered cellular and molecular mechanisms by which Notch signaling favors the efficient generation of effector CD8+ T cells. Fibroblastic reticular cells from secondary lymphoid organs, but not dendritic cells, were the dominant source of Notch signals in T cells via Delta-like1/4 ligands within the first 3 days of immune responses to vaccination or infection. Using transcriptional and epigenetic studies, we identified a unique Notch-driven T cell-specific signature. Early Notch signals were associated with chromatin opening in regions occupied by bZIP transcription factors, specifically BATF, known to be important for CD8+ T cell differentiation. Overall, we show that fibroblastic reticular cell niches control the ultimate molecular and functional fate of CD8+ T cells after vaccination or infection through the delivery of early Notch signals.
Authors
- Hélène Decaluwe (ORCID: https://orcid.org/0000-0001-6617-0633)
- Dave Maurice De Sousa (ORCID: https://orcid.org/0000-0002-4691-4655)
- Joshua D. Brandstadter (ORCID: https://orcid.org/0000-0003-0652-5791)
- Laure Le Corre (ORCID: https://orcid.org/0000-0001-7492-4693)
- Burkhard Ludewig (ORCID: https://orcid.org/0000-0002-7685-573X)
- Ivan Maillard (ORCID: https://orcid.org/0000-0003-1312-6748)
- Eric Perkey (ORCID: https://orcid.org/0000-0003-3275-3181)
- Nathalie Labrecque (ORCID: https://orcid.org/0000-0001-7563-1542)
- Daniela Gómez (ORCID: https://orcid.org/0000-0001-6015-339X)
- Freddy Radtke (ORCID: https://orcid.org/0000-0003-4315-4045)
- Frédéric Duval
- Jean‐François Daudelin
- Salix Boulet (ORCID: https://orcid.org/0000-0002-8446-8908)
- Christian W. Siebel (ORCID: https://orcid.org/0000-0003-4333-3756)
- Ute Koch (ORCID: https://orcid.org/0000-0001-7914-7061)
- Anneka Allman (ORCID: https://orcid.org/0000-0001-5335-2243)
- Katlyn Lederer (ORCID: https://orcid.org/0000-0003-2713-6664)
- Livia Odagiu (ORCID: https://orcid.org/0000-0002-8078-9114)
- Sarah Mezrag
- Myriam Ennajimi
- Marion Sarrias
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- University of Michigan (US)
- Kantonsspital St. Gallen (CH)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Hôpital Maisonneuve-Rosemont (CA)
- Montreal Clinical Research Institute (CA)
- École Polytechnique Fédérale de Lausanne (CH)
- Université de Montréal (CA)
- University of Pennsylvania (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1084/jem.20231758
- Citations
- 1
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- American Society for Transplantation and Cellular Therapy
- Université de Montréal
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases