TY - JOUR
T1 - Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development
AU - Dege, Carissa
AU - Fegan, Katherine H.
AU - Creamer, J. Philip
AU - Berrien-Elliott, Melissa M.
AU - Luff, Stephanie A.
AU - Kim, Darren
AU - Wagner, Julia A.
AU - Kingsley, Paul D.
AU - McGrath, Kathleen E.
AU - Fehniger, Todd A.
AU - Palis, James
AU - Sturgeon, Christopher M.
N1 - Funding Information:
C.D. J.P.C. M.M.B.-E. S.A.L. and J.A.W. are supported by an NHLBI T32 training grant (HL007088-41). C.M.S. was supported by an American Society of Hematology Scholar Award. K.H.F. P.D.K. K.E.M. and J.P. were supported in part by NIH R01 (DK09361) and by institutional pilot funding from the University of Rochester. T.A.F. was supported by NIH R01CA205239 and P50CA171963. M.M.B.-E. was supported by 5K12CA167540. This work was supported by grants from the American Cancer Society (IRG-58-010-59-2), the NIH/National Center for Advancing Translational Sciences (NCATS; UL1TR002345), a seed grant from the Washington University Center of Regenerative Medicine, and by institutional funding from the University of Rochester. We acknowledge the technical expertise of Leah Vit and support from the Michael Napoleon Memorial Foundation. Electron microscopy was performed at the Washington University Center for Cellular Imaging (WUCCI). Transcriptome analyses were performed at the Genome Technology Access Center (GTAC). C.D. J.P.C. S.A.L. M.M.B.-E. J.A.W. K.E.M. T.A.F. J.P. and C.M.S. designed the experiments and analyzed the data; C.D. K.H.F. D.K. P.D.K. and K.E.M. performed the experiments; C.D. J.P. K.E.M. and C.M.S. wrote the manuscript. The authors declare no competing interests.
Funding Information:
C.D., J.P.C., M.M.B.-E., S.A.L., and J.A.W. are supported by an NHLBI T32 training grant ( HL007088-41 ). C.M.S. was supported by an American Society of Hematology Scholar Award. K.H.F., P.D.K., K.E.M., and J.P. were supported in part by NIH R01 ( DK09361 ) and by institutional pilot funding from the University of Rochester . T.A.F. was supported by NIH R01CA205239 and P50CA171963 . M.M.B.-E. was supported by 5K12CA167540 . This work was supported by grants from the American Cancer Society ( IRG-58-010-59-2 ), the NIH/ National Center for Advancing Translational Sciences (NCATS; UL1TR002345 ), a seed grant from the Washington University Center of Regenerative Medicine, and by institutional funding from the University of Rochester . We acknowledge the technical expertise of Leah Vit and support from the Michael Napoleon Memorial Foundation . Electron microscopy was performed at the Washington University Center for Cellular Imaging (WUCCI). Transcriptome analyses were performed at the Genome Technology Access Center (GTAC).
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/4/20
Y1 - 2020/4/20
N2 - Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from Hoxaneg/low Kit+CD41+CD16/32+ hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXAneg/low CD34+ progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA+ CD34+ progenitors, as well as human cord blood CD34+ cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.
AB - Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from Hoxaneg/low Kit+CD41+CD16/32+ hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXAneg/low CD34+ progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA+ CD34+ progenitors, as well as human cord blood CD34+ cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.
KW - EMP
KW - HSC-independent
KW - adoptive immunotherapy
KW - definitive hematopoiesis
KW - erythro-myeloid progenitor
KW - human pluripotent stem cells
KW - natural killer cells
KW - ontogeny
KW - primitive hematopoiesis
KW - yolk sac
UR - http://www.scopus.com/inward/record.url?scp=85083279627&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2020.02.016
DO - 10.1016/j.devcel.2020.02.016
M3 - Article
C2 - 32197069
AN - SCOPUS:85083279627
SN - 1534-5807
VL - 53
SP - 229-239.e7
JO - Developmental Cell
JF - Developmental Cell
IS - 2
ER -