Mechanisms of CD40-dependent cDC1 licensing beyond costimulation

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. CD40 is typically understood as a costimulatory molecule. Here, the authors show CD4(+) T cell-induced CD40 signaling in conventional type 1 dendritic cells results in complicated gene expression that can enhance CD8(+) T cell priming by various underappreciated and independent mechanisms.

Automated summary

CD40 signaling in cDC1s plays a crucial role in anti-tumor immunity. It not only induces costimulatory ligands for CD8(+) T cells, but also induces Bcl2l1 that sustains cDC1 survival during the priming of the anti-tumor responses.