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.
Early Notch signals from fibroblastic reticular cells program effector CD8+ T cell differentiation
D. Maurice De Sousa, E. Perkey, and L. Le Corre are co-first authors.
Disclosures: D. Gómez Atria reported personal fees from Aro Biotherapeutics and GlaxoSmithKline outside the submitted work. J.D. Brandstadter reported personal fees from Recordati during the conduct of the study. C.W. Siebel reported personal fees from Genentech during the conduct of the study and personal fees from Genentech outside the submitted work. I. Maillard reported grants from NIAID and grants from NCI during the conduct of the study; "other" from Regeneron, Genentech, and Garuda Therapeutics; and grants from the Commonwealth of Pennsylvania outside the submitted work. N. Labrecque reported personal fees from The Journal of Immunology outside the submitted work. No other disclosures were reported.
