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Human fetal lymphoid tissue–inducer cells are interleukin 17–producing precursors to RORC+ CD127+ natural killer–like cells

Abstract

The human body contains over 500 individual lymph nodes, yet the biology of their formation is poorly understood. Here we identify human lymphoid tissue–inducer cells (LTi cells) as lineage-negative RORC+ CD127+ cells with the functional ability to interact with mesenchymal cells through lymphotoxin and tumor necrosis factor. Human LTi cells were committed natural killer (NK) cell precursors that produced interleukin 17 (IL-17) and IL-22. In vitro, LTi cells gave rise to RORC+ CD127+ NK cells that retained the ability to produce IL-17 and IL-22. Postnatally, similar populations of LTi cell–like cells and RORC+ CD127+ NK cells were present in tonsils, and both secreted IL-17 and IL-22 but no interferon-γ. Our data indicate that lymph node organogenesis is controlled by an NK cell precursor population with adaptive immune features and demonstrate a previously unappreciated link between the innate and adaptive immune systems.

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Figure 1: LinCD127+ cells in first-trimester mesentery and second-trimester lymph nodes.
Figure 2: LinCD45intCD127hi cells express RORC and LTi cell–associated genes.
Figure 3: The fetal lymph node–derived CD4+CD3 population does not contain LTi cells.
Figure 4: LinCD45intCD127hi cells have a functional lymphoid tissue–inducing ability.
Figure 5: LTi cells are precursors of CD127+ RORC-expressing NK cells.
Figure 6: CD127+ NK cells express RORC and produce IL-17A and IL-22.
Figure 7: Postnatal tonsils contain LTi cell–like cells that produce IL-22.
Figure 8: Activated tonsil-derived LTi cells and CD127+ NK cells produce IL-17 and IL-22 but not IFN-γ.

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Acknowledgements

We thank the staff of the Centers for Contraception, Sexual Health and Abortion in Leiden and Rotterdam and the Bloemenhove clinic in Heemstede for collection of fetal tissues; Y. Simons-Oosterhuis for help with quantitative PCR; M. Kuijf for acquiring tonsil tissue; and J. Samsom, R. Mebius, L. Lanier, L. Meyaard and members of the Hematology department of the Erasmus University Medical Center for critical reading of the manuscript. Supported by The Netherlands Organization for Scientific Research (VENI grant 916.66.018 to T.C.).

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T.C. and H.S. conceived the work; T.C. designed and did experiments for Figures 1, 2, 3, 4, 5, 6, 7, analyzed results and wrote the manuscript; N.K.C. designed, did and analyzed experiments for Figure 8; N.P. did experiments for Figures 1, 2, 3, 4, 5, 6, 7; E.J.R. assisted in flow cytometry and experimental procedures; K.W. isolated fetal organs; J.L.G. constructed the LTβR-Ig fusion protein; W.E.F. provided mesenchymal stem cells; J.J.C. assisted with the design of the experiments and interpretation of the data; H.S. designed experiments, analyzed data and cowrote the manuscript; and all authors read and provided comments on the manuscript.

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Correspondence to Tom Cupedo.

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N.K.C., J.L.G. and H.S. are employees of Genentech, a company that develops and markets therapeutic drugs.

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Cupedo, T., Crellin, N., Papazian, N. et al. Human fetal lymphoid tissue–inducer cells are interleukin 17–producing precursors to RORC+ CD127+ natural killer–like cells. Nat Immunol 10, 66–74 (2009). https://doi.org/10.1038/ni.1668

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