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TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy

An Erratum to this article was published on 19 July 2013

This article has been updated

Abstract

A large gap in our understanding of infant immunity is why natural killer (NK) cell responses are deficient, which makes infants more prone to viral infection. Here we demonstrate that transforming growth factor-β (TGF-β) was responsible for NK cell immaturity during infancy. We found more fully mature NK cells in CD11cdnR mice, whose NK cells lack TGF-β receptor (TGF-βR) signaling. Ontogenic maturation of NK cells progressed faster in the absence of TGF-β signaling, which results in the formation of a mature NK cell pool early in life. As a consequence, infant CD11cdnR mice efficiently controlled viral infections. These data thus demonstrate an unprecedented role for TGF-β in ontogeny that can explain why NK cell responses are deficient early in life.

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Figure 1: TGF-β is a negative regulator of NK cell generation.
Figure 2: CD11cdnR mice produce large numbers of stage F mNK cells.
Figure 3: Massive production of stage F mNK cells in CD11cdnR mice is cell-autonomous.
Figure 4: TGF-β arrests NK cell cycle at stages D and E and limits NK cell transition at stage F.
Figure 5: TGF-β imposes constraints on maturation of NK cells during ontogeny.
Figure 6: Infant CD11cdnR mice have mature NK cell compartment.
Figure 7: Infant CD11cdnR mice are protected from MCMV infection.

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Gene Expression Omnibus

Change history

  • 15 January 2013

    In the version of this article initially published, the key in Figure 4e was omitted. The correct key defines "Expression (fold)" as red (–4) to green (4). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. Laouar for critical reading of the manuscript; I. Maillard (University of Michigan) for OP9 cell line; D. Kovarcik and B. Oliver for assistance with gene expression analysis; and members of the flow cytometry core facility for cell sorting. Supported by the US National Institute of Health (T32 AI007413-17 to K.L.S. and R01 AI083642 to Y.L.).

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J.P.M., J.R.L., K.L.S., M.M. and A.R.F. performed and analyzed experiments; A.L.M. conducted gene expression array experiments; N.F.-C. performed MCMV plaque assay; S.M.V. provided reagents and advice on MCMV experiments; and Y.L. designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Yasmina Laouar.

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The authors declare no competing financial interests.

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Marcoe, J., Lim, J., Schaubert, K. et al. TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol 13, 843–850 (2012). https://doi.org/10.1038/ni.2388

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