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The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells

Nature Immunology volume 10, pages 306–313 (2009)Cite this article

Abstract

The influence of signals transmitted by the phosphatase calcineurin and the transcription factor NFAT on the development and function of natural killer T (NKT) cells is unclear. In this report, we demonstrate that the transcription factor early growth response 2 (Egr2), a target gene of NFAT, was specifically required for the ontogeny of NKT cells but not that of conventional CD4+ or CD8+ T cells. NKT cells developed normally in the absence of Egr1 or Egr3, which suggests that Egr2 is a specific regulator of NKT cell differentiation. We found that Egr2 was important in the selection, survival and maturation of NKT cells. Our findings emphasize the importance of the calcineurin-NFAT-Egr2 pathway in the development of the NKT lymphocyte lineage.

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Figure 1: The calcineurin-NFAT pathway is required for the development of NKT cells.
Figure 2: Egr2−/− mice have a severe defect in NKT cell development.
Figure 3: Egr2 is required for the productive selection and terminal maturation of NKT cells.
Figure 4: Similar CD1d expression and presentation of endogenous glycolipid by thymocytes from Egr2−/− and wild-type fetal liver chimeras.
Figure 5: Egr2−/− NKT cells have more proliferation and apoptosis.

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Acknowledgements

We thank D. Kozoriz for cell sorting; the National Institutes of Health Tetramer Core Facility at Emory University for unloaded and PBS57-loaded CD1d tetramers; J. Milbrandt (Washington University) for Egr2+/− and Egr3−/− mice; and M. Brenner (Harvard Medical School) and M. Brigl (Harvard Medical School) for the human NKT cell clone BM2a.3. Supported by the National Institutes of Health (PONS038037 and UOAI31541 to L.H.G.) and the Cancer Research Institute (V.L.)

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Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, 02115, Massachusetts, USA

    Vanja Lazarevic, Alfred J Zullo, Michelle N Schweitzer, Tracy L Staton & Laurie H Glimcher

  2. Howard Hughes Medical Institute and the Department of Pathology, Stanford University, Stanford, 94305, California, USA

    Elena M Gallo & Gerald R Crabtree

  3. Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Laurie H Glimcher

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Contributions

V.L. designed and did experiments and prepared the manuscript; A.J.Z. and T.L.S. contributed to discussions, experimental design and manuscript preparation; A.J.Z. and M.N.S. provided technical assistance; L.H.G. supervised the work and the manuscript preparation; and G.R.C. and E.M.G. provided Cnb1fl/fl Lck-Cre+ mice.

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Correspondence to Laurie H Glimcher.

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L.H.G. is on the board of directors and holds equity in Bristol Myers Squibb.

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Lazarevic, V., Zullo, A., Schweitzer, M. et al. The gene encoding early growth response 2, a target of the transcription factor NFAT, is required for the development and maturation of natural killer T cells. Nat Immunol 10, 306–313 (2009). https://doi.org/10.1038/ni.1696

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