cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity

Abstract

Conventional type 1 dendritic cells (cDC1s 1 ) are thought to perform antigen cross-presentation required to prime CD8 T cells 2 , 3 , while cDC2 are considered specialized for priming CD4 T cells 4 , 5 . CD4 T cells are also thought to help CD8 T cell responses through a variety of mechanisms 6 – 11 , including a model in which CD4 T cells ‘license’ cDC1 for CD8 T cell priming 12 . However, this model has not been directly tested in vivo or in the setting of a help-dependent tumour rejection. Here, we generated an Xcr1 -Cre mouse strain to evaluate the cellular interactions that mediate tumour rejection in a model requiring CD4 and CD8 T cells. As expected, tumour rejection required cDC1, and expression of MHC-I by cDC1. Unexpectedly, early priming of CD4 T cell against tumour-derived antigens also required cDC1, which was not simply due to a role in antigen transport to lymph nodes for processing by cDC2, since selective deletion of MHC-II in cDC1 also prevented early CD4 T cell priming. Further, deletion of either MHC-II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4 T cell interactions and CD40 signaling in cDC1 licensing. Finally, CD40 signaling in cDC1 was critical not only for CD8 T cell priming, but also for initial CD4 T cell activation. Thus, in the setting of tumour-derived antigens, cDC1 function as an autonomous platform capable of antigen processing and priming for both CD4 and CD8 T cells and directly orchestrating their cross-talk required for optimal anti-tumour immunity.

cDC1 and interferons promote spontaneous CD4+ and CD8+ T cell protective responses to breast cancer

“…Together with our observation of the simultaneous interactions of cDC1 with CD4 + T cells and CTLs in the tumor bed, this suggested that cell-intrinsic responses of cDC1 to IFN may be critical to promote their ability to deliver to CTL the help from CD4 + Tconv in a manner depending on their interactions via CD40/CD40L. This hypothesis is consistent with the demonstration that simultaneous presentation of viral antigens by cDC1s to CTLs and CD4 + T cells is key for robust antiviral cellular immunity (49,50) and with publications linking CD40 expression on cDC1, their ability to activate CD4 + Tconv and the CTL-dependent rejection of tumors (14,51).…”

“…IL-12 production and IL-15 trans-presentation promote CTL IFN-γ expression and proliferation. cDC1 could also promote delivery to CTLs of help from other immune cells including CD4 + T cells (5,14). However, which of these output signals are critical for cDC1 antitumor immunity remains to be rigorously investigated (5,15).…”

The role of dendritic cells in tumor microenvironments and their uses as therapeutic targets

“…However, cDC2s are involved in antitumor immune responses by inducing the proliferation of antitumor CD4 + T cells ( 12 ). A recent study showed that both CD4 + and CD8 + T cells are required for tumor rejection and selective deletion of MHC class II in cDC1s, as well as inhibition of early CD4 + T-cell priming, suggesting that cDC1s and cDC2s are required for CD4 + T-cell priming ( 13 ).…”

Dendritic Cells: Behind the Scenes of T-Cell Infiltration into the Tumor Microenvironment

“…Unlike cDC1s, the role of cDC2s in cancer immunity is less defined. cDC2s are the most important subset of human DCs in blood, lymphoid organs and non-lymphoid tissues, as well as the most efficient APCs for CD4 + T-cell activation and expansion [ 32 ]. cDC2s also express different markers in mouse and human ( Table 1 ).…”