TY - JOUR
T1 - Transcriptional Basis of Mouse and Human Dendritic Cell Heterogeneity
AU - Brown, Chrysothemis C.
AU - Gudjonson, Herman
AU - Pritykin, Yuri
AU - Deep, Deeksha
AU - Lavallée, Vincent Philippe
AU - Mendoza, Alejandra
AU - Fromme, Rachel
AU - Mazutis, Linas
AU - Ariyan, Charlotte
AU - Leslie, Christina
AU - Pe'er, Dana
AU - Rudensky, Alexander Y.
N1 - Funding Information:
We thank our lab members for technical support and discussion, Jacob Verter and Jian Hu for assistance with tissue preparations, Virginia Pascuale for provision of human PBMCs. This work was supported by Wellcome Trust, the Ludwig Center at Memorial Sloan Kettering, Parker Institute for Cancer Immunotherapy (PICI), NCI Cancer Center (support grant P30 CA08748), and the Hilton-Ludwig Cancer Prevention Initiative (Conrad N. Hilton Foundation and Ludwig Cancer Research). A.Y.R. is an HHMI investigator. C.C.B. is a Wellcome Trust Fellow. Y.-P.L. was supported by MSKCC PICI-Cycle for Survival Fund. D.D. was supported by a Medical Scientist Training Program grant from the NIGMS. C.C.B. and A.Y.R. conceived the study, designed experiments, and wrote the manuscript. C.C.B. and D.D. performed experiments and analyzed data. A.M. assisted with cytological analysis. H.G. designed and performed analyses on single-cell transcriptomes. Y.-P.L. designed and performed bulk RNA-seq and ATAC-seq analyses. V.L. analyzed human melanoma scRNA-seq. L.M. advised on design of scRNA-seq experiments. C.A. provided melanoma samples. R.F. processed human samples. C.L. and D.P. supervised computational analyses. The authors declare no competing interests.
Funding Information:
We thank our lab members for technical support and discussion, Jacob Verter and Jian Hu for assistance with tissue preparations, Virginia Pascuale for provision of human PBMCs. This work was supported by Wellcome Trust , the Ludwig Center at Memorial Sloan Kettering , Parker Institute for Cancer Immunotherapy (PICI), NCI Cancer Center (support grant P30 CA08748 ), and the Hilton-Ludwig Cancer Prevention Initiative (Conrad N. Hilton Foundation and Ludwig Cancer Research). A.Y.R. is an HHMI investigator. C.C.B. is a Wellcome Trust Fellow. Y.-P.L. was supported by MSKCC PICI-Cycle for Survival Fund. D.D. was supported by a Medical Scientist Training Program grant from the NIGMS .
Publisher Copyright:
© 2019 The Authors
PY - 2019/10/31
Y1 - 2019/10/31
N2 - Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.
AB - Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.
KW - ATAC-sequencing
KW - T-bet
KW - dendritic cells
KW - myeloid cells
KW - single-cell RNA-sequencing
KW - transcriptional regulation
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U2 - 10.1016/j.cell.2019.09.035
DO - 10.1016/j.cell.2019.09.035
M3 - Article
C2 - 31668803
AN - SCOPUS:85074017183
VL - 179
SP - 846-863.e24
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -