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 mechanisms6,7,8,9,10,11, 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.
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Data availability
The microarray data generated during the course of this study have been deposited and are available at the Gene Expression Omnibus (GEO) database. The microarrays used in Fig. 4b and Extended Data Fig. 7b can be accessed with the accession number GSE152196. All other primary data and materials that support the findings of this study are available from the corresponding author upon request. Source data are provided with this paper.
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Acknowledgements
K.M.M. was supported by the Howard Hughes Medical Institute and the US National Institutes of Health (R01AI150297); R.D.S. by grants from the National Institutes of Health (R01CA190700) and The Parker Institute for Cancer Immunotherapy, and a Stand Up To Cancer–Lustgarden Foundation Pancreatic Cancer Foundation Convergence Team Translational Research Grant; W.M.Y. by a grant from the National Institutes of Health (R01AI129545); M.D.B. and V.D. by fellowship grants from the National Institutes of Health (F30DK112466 and F30DK108498, respectively); S.T.F. by a postdoctoral training grant from the National Institutes of Health (T32CA95473); G.F.W., D.J.T. and J.T.D. by the National Institutes of Health (R01NS106289, T32 AI007163 and T32CA009621, respectively); and P.B. by the US National Science Foundation (DGE-1143954). We thank the Genome Technology Access Center, Department of Genetics, Washington University School of Medicine in St Louis, for help with genomic analysis. The Center is supported by Cancer Center Support Grant P30 CA91842 from the US National Cancer Institute and by Institute of Clinical and Translational Sciences/Clinical and Translational Science Award UL1 TR000448 from the US National Center for Research Resources. Aspects of studies including tetramer production were performed with assistance by the Immunomonitoring Laboratory, which is supported by the Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs and the Alvin J. Siteman Comprehensive Cancer Center that, in turn, is supported by the National Cancer Institute of the National Institutes of Health Cancer Center Support Grant (P30CA91842) and the Washington University Rheumatic Diseases Research Resource-based Center Grant (P30AR073752).
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S.T.F., R.W. and V.D. conceived and designed the experiments, collected the data, and performed and interpreted the analyses. S.T.F. and R.W. wrote the manuscript. J.T.D., P.B., D.J.T., T.L., L.L. and C.G.B. collected and analysed data. J.P.W. and D.J.T. helped generate the 1956-mOVA fibrosarcoma cell line. M.D.B. provided the β2mfl/fl mouse and interpreted the analyses. G.F.W., W.M.Y., W.E.G., T.L.M. and R.D.S. provided assistance with experimental design. K.M.M. conceived experiments, interpreted data, and wrote the manuscript.
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R.D.S. is a cofounder, scientific advisory board member, stockholder and royalty recipient of Jounce Therapeutics and Neon Therapeutics and is a scientific advisory board member for A2 Biotherapeutics, BioLegend, Codiak Biosciences, Constellation Pharmaceuticals, NGM Biopharmaceuticals and Sensei Biotherapeutics.
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Extended data figures and tables
Extended Data Fig. 1 cDC1 are required to prime CD4+ T cells during the tumour immune response.
a, 1956-EV and 1956-mOVA were stained with antibodies against (left) Thy1.1 and (right) OVA. b, Tumour growth curves of B6 wild-type (WT) mice injected with 106 (left)1956-EV or (right)1956-mOVA. c, Tumour growth curves of (left) B6 WT or (right) Irf8 +32–/– mice injected with 106 1956-mOVA. d, B6 WT or Irf8 +32–/– mice were subcutaneously injected with 106 1956-EV or 106 1956-mOVA. Spleens were isolated and stained for presence of SIINFEKL-Kb-tetramer+ CD8+ T cells. (Left) Representative flow plots of percentage of tetramer+ CD8+ T cells. (Right) Graph of tetramer+ CD8+ T cells as a percentage of all T cells. Data are pooled biologically independent samples from two independent experiments (n = 3 for WT EV, n = 4 for WT 1956-mOVA, n = 5 for Irf8 +32–/– 1956-mOVA).
Extended Data Fig. 2 cDC1 are required to prime CD4+ T cells during the immune response to B16F10 melanoma.
a, B16F10-EV and B16F10-mOVA were stained with antibodies against (left) Thy1.1 and (right) OVA. b, B6 WT or Irf8 +32–/– mice were subcutaneously injected with 106 B16F10-EV or 106 B16F10-mOVA. (Left) Representative flow plots of OT-II T cells 3 days after transfer. (Right) Graph of per cent proliferated OT-II transferred. Data are pooled biologically independent samples from two independent experiments (n = 4 for WT B16F10-EV, n = 6 for all other groups).*P = 0.04 (unpaired, two-tailed Mann–Whitney test).
Extended Data Fig. 3 Validation of mCherry expression and lineage tracing of Xcr1Cre mouse.
a, Schematic diagrams of the mouse Xcr1 WT allele, the targeting vector (IRES-mCherry-T2a-hCRE with FRT flanked pGK-Neo cassettes), and the targeted allele. Filled and open boxes denote coding and noncoding exons of Xcr1, respectively. b, Southern blot analysis of Xcr1+/+ and Xcr1Cre/+. Genomic DNAs were isolated from mice tails, digested with SalI, electrophoresed, and hybridized with the 5′-radiolabelled probe indicated in a. Southern blot gave a 10.6 and a 6.9 kbp band for WT and targeted allele, respectively. For Southern blot source data, see Supplementary Fig. 1. c, Southern blot analysis of Xcr1+/+ and Xcr1Cre/+. Genomic DNAs were isolated from mice tails, digested with SalI, electrophoresed, and hybridized with the 3′ radiolabelled probe indicated in a. Southern blot gave a 10.6 and a 8.2 kbp band for WT and targeted allele, respectively. For Southern blot source data, see Supplementary Fig. 1. d, Gating strategy to delineate splenic cell populations. e, FACs histograms of mCherry expression from subpopulations in d isolated from Xcr1Cre/+ and Xcr1+/+ mice. f, Graph of mCherry expression in antigen-presenting cell populations gated from d isolated from Xcr1Cre/+ and Xcr1+/+ mice. Data are pooled biologically independent samples from two independent experiments (n = 5 in all groups). g, FACs histograms for YFP expression from subpopulations in d isolated from Xcr1Cre/+ R26LSLYFP/+ and Xcr1+/+ R26LSLYFP/+ mice. h, Graph of YFP expression in splenic cell populations (Mo, monocytes; N, neutrophils; RPM, red pulp macrophages). Data are pooled biologically independent samples from two independent experiments (n = 6 for cDC1, cDC2, plasmacytoid dendritic cells (pDC) and B cells from Xcr1+/+ R26LSLYFP/+ mice, n = 7 for cDC1, cDC2, pDC and B cells from Xcr1Cre/+ R26LSLYFP/+ mice, and n = 4 for all other groups). i, (Top) Gating strategy to delineate SDLN cell populations. (Bottom) FACs histograms for YFP expression in cDC1 and cDC2 isolated from Xcr1Cre/+ R26LSLYFP/+ and Xcr1+/+ R26LSLYFP/+ mice. j, Graph of YFP expression from subpopulations in i isolated from Xcr1Cre/+ R26LSLYFP/+ and Xcr1+/+ R26LSLYFP/+ mice. Data are pooled biologically independent samples from two independent experiments (n = 3 in all groups).
Extended Data Fig. 4 Proliferation of OT-I in Xcr1Cre/+ β2mfl/fl mice receiving soluble or cell-associated OVA.
a, Representative FACs analysis and histograms of CFSE dilution of proliferated OT-I on day 3 after transfer into (left) Xcr1+/+ β2mfl/fl and (right) Xcr1Cre/+ β2mfl/fl immunized with soluble OVA. b, Graph of per cent proliferation of transferred OT-I in mice immunized with soluble OVA. Data are pooled biologically independent samples from two independent experiments (n = 5 for all groups). c, Representative FACs analysis and histograms of CFSE dilution of proliferated OT-I on day 3 after transfer into (left) Xcr1+/+ β2mfl/fl and (right) Xcr1Cre/+ β2mfl/fl immunized with cell-associated OVA. d, Graph of per cent proliferation of transferred OT-I in mice immunized with cell-associated OVA. Data are pooled biologically independent samples from two independent experiments (n = 5 Xcr1+/+ β2mfl/fl –OVA, n = 6 for Xcr1Cre/+ β2mfl/fl +OVA, n = 7 for Xcr1+/+ β2mfl/fl +OVA, and n = 8 for Xcr1Cre/+ β2mfl/fl +OVA).
Extended Data Fig. 5 Proliferation of OT-II in Xcr1Cre /+ MHCIIfl/fl and Xcr1Cre /+ MHCIILSL/– mice immunized with soluble and cell-associated OVA.
a, Representative FACS analysis of splenic CD4+ T cell percentage in WT B6, Xcr1+/+ MHCIILSL/–, and Xcr1Cre/+ MHCIILSL/– mice at steady state. b, (Left) Representative FACS analysis of splenic Treg percentage in Xcr1+/+ MHCIIfl/fl and Xcr1Cre/+ MHCIIfl/fl at steady state. (Right) Graph of splenic Treg percentage as a percentage of all CD4+ T cells. Data are pooled biologically independent samples from two independent experiments (n = 5 for Xcr1+/+ MHCIIfl/fl, n = 4 for Xcr1Cre/+ MHCIIfl/fl). c, Representative FACs analysis and histograms of CFSE dilution of proliferated OT-II on day 3 after transfer into Xcr1+/+ MHCIIfl/fl, Xcr1Cre/+ MHCIIfl/fl, and Xcr1Cre/+ MHCIILSL/– immunized with soluble OVA. d, Representative FACs analysis and histograms of CFSE dilution of proliferated OT-II on day 3 after transfer into Xcr1+/+ MHCIIfl/fl, Xcr1Cre/+ MHCIIfl/fl, and Xcr1Cre/+ MHCIILSL/– immunized with cell-associated OVA.
Extended Data Fig. 6 Analysis of cDC1 in conditionally deleted mice.
a, Graph of splenic cDC1 percentage in Xcr1+/+ β2mfl/fl and Xcr1Cre/+ β2mfl/fl. Data are pooled biologically independent samples from two independent experiments (n = 5 for all groups). P = NS (unpaired, two-tailed Mann–Whitney test). b, Graph of splenic cDC1 percentage in Xcr1+/+ MHCIIfl/fl and Xcr1Cre/+ MHCIIfl/fl. Data are pooled biologically independent samples from two independent experiments (n = 5 for all groups). P = NS (unpaired, two-tailed Mann–Whitney test). c, Graph of absolute numbers of transferred OT-I in soluble OVA treated Xcr1+/+ β2mfl/fl and Xcr1Cre/+ β2mfl/fl mice. Data are pooled biologically independent samples from two independent experiments (n = 5 for all groups). d, Graph of absolute numbers of transferred OT-II in soluble OVA treated Xcr1+/+ MHCIIfl/fl and Xcr1Cre/+ MHCIIfl/fl mice. Data are pooled biologically independent samples from two independent experiments (n = 5 for all groups). e, Graph of per cent proliferated OT-I in cell-associated treated Xcr1+/+ MHCIIfl/fl and Xcr1Cre/+ MHCIIfl/fl mice. Data are pooled biologically independent samples from two independent experiments (n = 6 for Xcr1Cre/+ MHCIIfl/fl OVA– and OVA+ and n = 5 for all other groups). f, Graph of per cent proliferation of OT-I after 72 h coculture with ex vivo migratory cDC2 or cDC1 collected from tumour-draining lymph nodes of Xcr1+/+ MHCIIfl/fl or Xcr1Cre/+ MHCIIfl/fl mice injected 6 days earlier with 106 1956-mOVA cells. Cells were cultured at a ratio of 10:1 naive OT-I:cDC. Data are pooled independent samples from two independent experiments (n = 4 for all groups). g, Graph of absolute number of proliferated OT-I per well after 72 h coculture with ex vivo migratory cDC2 or cDC1 collected from tumour-draining lymph nodes of Xcr1+/+ MHCIIfl/fl, Xcr1Cre/+ MHCIIfl/fl mice six days after injection with 106 1956-mOVA. Cells were cultured at 10:1 ratio of naive OT-I:cDC. Data are pooled independent samples from two independent experiments (n = 4 for all groups).
Extended Data Fig. 7 CD40 deficiency does not affect cDC1 development.
a, SDLN flow cytometry gating for cDC1 expression of CD40. Migratory cDC1 (CD11cint MHCIIhi; Red) were overlaid for expression with resident cDC1 (CD11chi MHCIIint; Blue). (Top) Xcr1+/+ CD40fl/fl and (bottom) Xcr1Cre/+ CD40fl/fl SDLN and splenic antigen-presenting cells stained for CD40 expression. b, Gene-expression data from Xcr1+/+ CD40fl/fl and Xcr1Cre/+ CD40fl/fl cDC1 from spleens and SDLN. Green lines indicate 2-fold changes. c, Graph of per cent proliferation of OT-I after 72 h coculture with ex vivo migratory cDC2 or cDC1 collected from tumour-draining lymph nodes of Xcr1+/+ CD40fl/fl or Xcr1Cre/+ CD40fl/fl mice injected 6 days earlier with 106 1956-mOVA cells. Cells were cultured at a ratio of 10:1 naive OT-I:cDC. Data are pooled independent samples from two independent experiments (n = 3 for Xcr1+/+ CD40fl/fl cDC2 and n = 4 for all other groups). d, Graph of per cent proliferation of OT-I in tumour-draining lymph node of tumour-bearing mice 3 days after transfer. Xcr1+/+ CD40fl/fl and Xcr1Cre/+ CD40fl/fl mice were injected with 106 1956-EV or 106 1956-mOVA. Data are pooled independent samples from two independent experiments (n = 5 for Xcr1Cre/+ CD40fl/fl1956-mOVA, n = 3 for all other groups). e, Graph of per cent proliferation of transferred OT-II in soluble OVA treated Xcr1+/+ CD40fl/fl and Xcr1Cre/+ CD40fl/fl mice. Data are pooled biologically independent samples from two independent experiments (n = 2 for 0 mg Xcr1+/+ CD40fl/fl and Xcr1Cre/+ CD40fl/fl and n = 4 for all other groups). f, Graph of per cent proliferation of OT-II in tumour-draining lymph node of tumour-bearing mice 3 days after transfer. Xcr1+/+ CD40fl/fl and Xcr1Cre/+ CD40fl/fl mice were injected with 106 1956-EV or 106 1956-mOVA. Data are pooled biologically independent samples from three independent experiments (n = 4 for 1956-EV, n = 6 for 1956-mOVA Xcr1+/+ CD40fl/fl, and n = 9 for 1956-mOVA Xcr1Cre/+ CD40fl/fl). g, Gating strategy to delineate day 6 1956-mOVA tumour immune cell antigen-presenting cell populations. h, FACs histogram of CD40 expression on gated antigen-presenting cell populations from e.
Extended Data Fig. 8 T cells are required at tumour site to induce memory.
a, Schematic of FTY720 injection during primary tumour response. b, Schematic of FTY720 injection during secondary tumour response. c, Peripheral blood CD4+ and CD8+ T cell percentage in control and FTY720 treated mice. Data represent mean ± s.d. pooled biologically independent samples from two independent experiments (n = 2 control, n = 5 FTY720). d, Tumour growth curves of mice injected with FTY720 during the primary or secondary 1956 tumour implantation. Data represent mean ± s.d. pooled biologically independent samples from two independent experiments (n = 4 for FTY720 1º and n = 5 for all other groups). e, Individual mouse tumour growth curves of control or FTY720 injected mice. f, (Left) Tumour growth curves of Xcr1+/+ MHCIIfl/fl and Xcr1Cre/+ MHCIIfl/fl mice during primary and secondary 1956 tumour implantation. Individual mouse tumour growth curves of (middle) Xcr1+/+ MHCIIfl/fl or (right) Xcr1Cre/+ MHCIIfl/fl mice during primary and secondary 1956 tumour implantation. Data represent mean ± s.d. pooled biologically independent samples from two independent experiments (n = 7 for Xcr1+/+ MHCIIfl/fl and n = 6 for Xcr1Cre/+ MHCIIfl/fl). g, (Left) Tumour growth curves of Xcr1+/+ CD40fl/fl and Xcr1Cre/+ CD40fl/fl mice during primary and secondary 1956 tumour implantation. Individual mouse tumour growth curves of (middle) Xcr1+/+ CD40fl/fl or (right) Xcr1Cre/+ CD40fl/fl mice during primary and secondary 1956 tumour implantation. Data represent mean ± s.d. pooled biologically independent samples from two independent experiments (n = 4 for Xcr1+/+ CD40fl/fl and n = 7 for Xcr1Cre/+ CD40fl/fl).
Extended Data Fig. 9 OT-II CD4+ T cells fail to localize to the tumour in Xcr1Cre/+ MHCIIfl/fl mice.
a, Graph of per cent accumulation of transferred OT-I in tumours of Xcr1+/+ β2mfl/fl, Xcr1Cre/+ β2mfl/fl injected with 106 1956-EV or 1956-mOVA on day 0. OT-I cells were transferred intravenously on day 2 and assessed as a percentage of total CD45+ cells on (left) day 5 and (right) day 7. Data represent pooled biologically independent samples from two independent experiments (n = 1 for Xcr1+/+ β2mfl/fl tdLN and tumour 1956-EV day 5, n = 4 for Xcr1+/+ β2mfl/fl 1956-mOVA tdLN and tumour Day 7 n = 2 for all other groups). b, Graph of per cent accumulation of transferred OT-I in tumours of Xcr1+/+ MHCIIfl/fl, Xcr1Cre/+ MHCIIfl/fl injected with 106 1956-EV or 1956-mOVA on day 0. OT-I cells were transferred intravenously on day 2 and assessed as a percentage of total CD45+ cells on (left) day 5 and (right) day 7. Data represent pooled biologically independent samples from two independent experiments (n = 4 for Xcr1+/+ MHCIIfl/fl tdLN and tumour 1956-mOVA day 7, n = 3 for Xcr1+/+ MHCIIfl/fl tdLN and tumour 1956-mOVA day 5 and for Xcr1+/+ MHCIIfl/fl tdLN and tumour 1956-EV Day 7, n = 2 for all other samples). c, Graph of per cent accumulation of transferred OT-II in tumours of Xcr1+/+ MHCIIfl/fl, Xcr1Cre/+ MHCIIfl/fl injected with 106 1956-EV or 1956-mOVA on day 0. OT-II cells were transferred intravenously on day 2 and assessed as a percentage of total CD45+ cells on (left) day 5 and (right) day 7. Data represent pooled biologically independent samples from two independent experiments (n = 6 for Xcr1+/+ MHCIIfl/fl tdLN and tumour 1956-mOVA day 7, n = 4 for Xcr1+/+ MHCIIfl/fl tdLN and tumour 1956-EV Day 7, n = 3 for Xcr1+/+ MHCIIfl/fl tdLN and tumour 1956-mOVA day 5, n = 2 for all other samples).
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Ferris, S.T., Durai, V., Wu, R. et al. cDC1 prime and are licensed by CD4+ T cells to induce anti-tumour immunity. Nature 584, 624–629 (2020). https://doi.org/10.1038/s41586-020-2611-3
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DOI: https://doi.org/10.1038/s41586-020-2611-3
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