TY - JOUR
T1 - Effector differentiation downstream of lineage commitment in ILC1s is driven by Hobit across tissues
AU - Friedrich, Christin
AU - Taggenbrock, Renske L. R. E.
AU - Doucet-Ladevèze, R. mi
AU - Golda, Gosia
AU - Moenius, Rebekka
AU - Arampatzi, Panagiota
AU - Kragten, Natasja A. M.
AU - Kreymborg, Katharina
AU - Gomez de Agüero, Mercedes
AU - Kastenmüller, Wolfgang
AU - Saliba, Antoine-Emmanuel
AU - Grün, Dominic
AU - van Gisbergen, Klaas P. J. M.
AU - Gasteiger, Georg
N1 - Funding Information: We thank C. Romagnani for critically reading the manuscript, and S. Klingler, M. Lian, S. Riedmann, L. Parga-Vidal and the IZKF FACS sorting facility Würzburg for expert technical assistance. We thank E. Vivier (Aix Marseille Univ., CNRS, INSERM, CIML, Marseille, France) and A. Rudensky (Howard Hughes Medical Institute, Immunology Program, and Ludwig Center, Memorial Sloan Kettering Cancer Center, New York, USA) for providing mice. We thank R. Naumann (MPI-CBG, Dresden) for providing Flp deleter mice and for microinjections of HobitKO ES cells. This work was supported by grants through the German Research Foundation (DFG) priority program SPP1937 – Innate lymphoid cells (GA2129/2-2 to G.Gasteiger and GR4980/1-2 to D.G.), through the European Research Council (759176-TissueLymphoContexts to G.Gasteiger, 818846-ImmuNiche to D.G. and 819329-STEP2 to W.K.). G.Gasteiger and D.G. are supported by the Max Planck Society. P.A. acknowledges financial support from Interdisciplinary Center for Clinical Research-IZKF (project Z-6). A.-E.S. is supported by the EMBO Young Investigator program. K.P.J.M.v.G. was funded by a LSBR fellowship from Landsteiner Foundation of Blood Transfusion Research (1629). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit+CD127hiTCF-1hi early differentiation stages of T-bet+ ILC1s. These cells were present across different organs and had the potential to mature toward CD127intTCF-1int and CD127−TCF-1− ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.
AB - Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit+CD127hiTCF-1hi early differentiation stages of T-bet+ ILC1s. These cells were present across different organs and had the potential to mature toward CD127intTCF-1int and CD127−TCF-1− ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.
UR - http://www.scopus.com/inward/record.url?scp=85113996658&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41590-021-01013-0
DO - https://doi.org/10.1038/s41590-021-01013-0
M3 - Article
C2 - 34462601
SN - 1529-2908
VL - 22
SP - 1256
EP - 1267
JO - Nature immunology
JF - Nature immunology
IS - 10
ER -