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

Stephen T. Ferris, Vivek Durai, Renee Wu, Derek J. Theisen, Jeffrey P. Ward, Michael D. Bern, Jesse T. Davidson, Prachi Bagadia, Tiantian Liu, Carlos G. Briseño, Lijin Li, Will Gillanders, Gregory F. Wu, Wayne M. Yokoyama, Theresa L. Murphy, Robert D. Schreiber, Kenneth M. Murphy

Research output: Contribution to journalArticle

Abstract

Conventional type 1 dendritic cells (cDC1)1 are thought to perform antigen cross-presentation, which is required to prime CD8+ T cells2,3, whereas cDC2 are specialized for priming CD4+ T cells4,5. CD4+ T cells are also considered to help CD8+ T cell responses through a variety of mechanisms6–11, including a process whereby 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 help-dependent tumour rejection. Here we generated an Xcr1Cre 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 CD8+ T cell priming required the expression of major histocompatibility class I molecules by cDC1. Unexpectedly, early priming of CD4+ T cells against tumour-derived antigens also required cDC1, and this was not simply because they transport antigens to lymph nodes for processing by cDC2, as selective deletion of major histocompatibility class II molecules in cDC1 also prevented early CD4+ T cell priming. Furthermore, deletion of either major histocompatibility class II or CD40 in cDC1 impaired tumour rejection, consistent with a role for cognate CD4+ T cell interactions and CD40 signalling in cDC1 licensing. Finally, CD40 signalling 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 of the direct orchestration of their cross-talk that is required for optimal anti-tumour immunity.

Original languageEnglish
Pages (from-to)624-629
Number of pages6
JournalNature
Volume584
Issue number7822
DOIs
StatePublished - Aug 27 2020

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    Ferris, S. T., Durai, V., Wu, R., Theisen, D. J., Ward, J. P., Bern, M. D., Davidson, J. T., Bagadia, P., Liu, T., Briseño, C. G., Li, L., Gillanders, W., Wu, G. F., Yokoyama, W. M., Murphy, T. L., Schreiber, R. D., & Murphy, K. M. (2020). cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity. Nature, 584(7822), 624-629. https://doi.org/10.1038/s41586-020-2611-3