CDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity.

Abstract

Conventional type 1 dendritic cells (cDC1s1) are thought to perform antigen cross-presentation required to prime CD8 T cells2,3, while cDC2 are considered specialized for priming CD4 T cells4,5. CD4 T cells are also thought to help CD8 T cell responses through a variety of mechanisms6–11, including a model in which CD4 T cells ‘license’ cDC1 for CD8 T cell priming12. 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.