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The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway

A Corrigendum to this article was published on 19 July 2013

This article has been updated

Abstract

NKp46+ innate lymphoid cells (ILCs) serve important roles in regulating the intestinal microbiota and defense against pathogens. Whether NKp46+ ILCs arise directly from lymphoid tissue–inducer (LTi) cells or represent a separate lineage remains controversial. We report here that the transcription factor T-bet (encoded by Tbx21) was essential for the development of NKp46+ ILCs but not of LTi cells or nuocytes. Deficiency in interleukin 22 (IL-22)-producing NKp46+ ILCs resulted in greater susceptibility of Tbx21−/− mice to intestinal infection. Haploinsufficient T-bet expression resulted in lower expression of the signaling molecule Notch, and Notch signaling was necessary for the transition of LTi cells into NKp46+ ILCs. Furthermore, NKp46+ ILCs differentiated solely from the CD4 LTi population, not the CD4+ LTi population. Our results pinpoint the regulation of Notch signaling by T-bet as a distinct molecular pathway that guides the development of NKp46+ ILCs.

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Figure 1: NKp46+ ILCs do not form in the absence of T-bet.
Figure 2: Loss of NKp46+ ILCs is not due to receptor regulation and is cell intrinsic.
Figure 3: T-bet is essential for resistance to infection with C. rodentium.
Figure 4: Notch and T-bet regulate the developmental pathway of innate lymphocyte populations.
Figure 5: CD4 LTi cells, not CD4+ LTi cells, give rise to NKp46+ ILCs.
Figure 6: Notch and T-bet regulate the developmental pathway of innate lymphocyte populations.

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Change history

  • 21 March 2013

    In the version of this article initially published, the key to Figure 1c was labeled incorrectly. The correct labeling is as follows: dotted line, Isotype; shaded box, T-bet. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank R. Robins-Browne, M. Camilleri, R. Cole, J. Cruickshank and the staff of the animal and flow cytometry facilities of the Walter and Eliza Hall Institute and Medical Research Council Laboratory of Molecular Biology for technical assistance. Supported by the National Health and Medical Research Council of Australia (G.T.B., S.L.N., S.C., L.R. and J.R.G.), the Sylvia and Charles Viertel Foundation (G.T.B.), the Howard Hughes Medical Institute (G.T.B.), the Australian Research Council (S.L.N.), the Leukaemia Foundation (M.J.H.), the American Asthma Foundation (J.A.W.), the Medical Research Council, the American Asthma Foundation (A.N.J.M.) and Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme.

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L.C.R., J.R.G., S.C., M.J.H., M.C., S.L.N. and G.T.B. designed and did experiments and analyzed data; L.A.M. did PCR analysis; J.A.W. and A.N.J.M. analyzed nuocytes; and G.T.B., L.C.R., J.R.G. and S.L.N. wrote the paper.

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Correspondence to Gabrielle T Belz.

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Supplementary Figures 1–6 and Tables 1–3 (PDF 1749 kb)

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Rankin, L., Groom, J., Chopin, M. et al. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nat Immunol 14, 389–395 (2013). https://doi.org/10.1038/ni.2545

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