Mechanisms of CD40-dependent cDC1 licensing beyond costimulation

• Type of Material: Article
• Authors: Renee Wu, Washington University in St. Louis; Ray A Ohara, Washington University in St. Louis; Suin Jo, Washington University in St. Louis; Tian-Tian Liu, Washington University in St. Louis; Stephen T Ferris, Washington University in St. Louis; Feiya Ou, Washington University in St. Louis; Sunkyung Kim, ]Washington University in St. Louis; Derek J Theisen, Washington University in St. Louis; David A Anderson, Washington University in St. Louis; Brian W Wong, Washington University in St. Louis; Timothy Gershon, Emory University; Robert D Schreiber, Washington University in St. Louis; Theresa L Murphy, Washington University in St. Louis; Kenneth M Murphy, Washington University in St. Louis
• Language: English
• Date: 2022-10-21
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-022-01324-w
• Title of Journal or Parent Work: NATURE IMMUNOLOGY
• Volume: 23
• Issue: 11
• Start Page: 1536
• End Page: +
• Keywords: DENDRITIC CELLS; Immunology; BCL-X-L; UP-REGULATION; CANCER-INDUCED APOPTOSIS; Science & Technology; B-CELL PROLIFERATION; Life Sciences & Biomedicine; IN-VITRO; CYTOTOXIC T-LYMPHOCYTES; ANTIVIRAL IMMUNITY; TRANSCRIPTION FACTOR; CD40

Abstract

CD40 signaling in classical type 1 dendritic cells (cDC1s) is required for CD8 T cell-mediated tumor rejection, but the underlying mechanisms are incompletely understood. Here, we identified CD40-induced genes in cDC1s, including Cd70, Tnfsf9, Ptgs2 and Bcl2l1, and examined their contributions to anti-tumor immunity. cDC1-specific inactivation of CD70 and COX-2, and global CD27 inactivation, only partially impaired tumor rejection or tumor-specific CD8 T cell expansion. Loss of 4-1BB, alone or in Cd27−/− mice, did not further impair anti-tumor immunity. However, cDC1-specific CD40 inactivation reduced cDC1 mitochondrial transmembrane potential and increased caspase activation in tumor-draining lymph nodes, reducing migratory cDC1 numbers in vivo. Similar impairments occurred during in vitro antigen presentation by Cd40−/− cDC1s to CD8+ T cells, which were reversed by re-expression of Bcl2l1. Thus, CD40 signaling in cDC1s not only induces costimulatory ligands for CD8+ T cells but also induces Bcl2l1 that sustains cDC1 survival during priming of anti-tumor responses.