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An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells

Nature Immunology volume 11, pages 240–249 (2010)Cite this article

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An Erratum to this article was published on 01 July 2010

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Abstract

E proteins are basic helix-loop-helix transcription factors that regulate many key aspects of lymphocyte development. Thymocytes express multiple E proteins that are thought to provide cooperative and compensatory functions crucial for T cell differentiation. Contrary to that, we report here that the E protein HEB was uniquely required at the CD4+CD8+ double-positive (DP) stage of T cell development. Thymocytes lacking HEB showed impaired survival, failed to make rearrangements of variable-α (Vα) segments to distal joining-α (Jα) segments in the gene encoding the T cell antigen receptor α-chain (Tcra) and had a profound, intrinsic block in the development of invariant natural killer T cells (iNKT cells) at their earliest progenitor stage. Thus, our results show that HEB is a specific and essential factor in T cell development and in the generation of the iNKT cell lineage, defining a unique role for HEB in the regulation of lymphocyte maturation.

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Figure 1: HEB is essential for iNKT cell development.
Figure 2: The defect in iNKT cell development by HEB-TKO thymocytes is cell intrinsic.
Figure 3: HEB deficiency influences the survival and proliferation of thymocytes.
Figure 4: Unique gene-expression profile of HEB-TKO DP cells.
Figure 5: Rearrangements of Vα to distal Jα segments are impaired in the absence of HEB.
Figure 6: Expression of a rearranged Vα14-Jα18 TCR transgene restores iNKT cell development in the absence of HEB.

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Change history

  • 12 March 2010

    In the version of this article initially published, references 35–41 were cited out of order in the text. The citations on page 247 should be as follows: column one, first paragraph, second full sentence, “RAG-2 recombinase protein35,36, which could in turn impair rearrangements37”; column two, middle paragraph, final two sentences, “iNKT development20-23,28,29,38,39....from stage 0 through stage 2 (refs. 20,38)”; column two, final paragraph, second sentence, “RORγt-deficient thymocytes40”; and column two, final paragraph, fourth sentence, “Tcra rearrangements33,34,41.” The reference list should be as follows: 37. Yannoutsos, N. et al. The role of recombination activating gene (RAG) reinduction in thymocyte development in vivo. J. Exp. Med. 194, 471–480 (2001). 38. Nichols, K.E. et al. Regulation of NKT cell development by SAP, the protein defective in XLP. Nat. Med. 11, 340–345 (2005). 39. Savage, A.K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008). 40. Benlagha, K., Wei, D.G., Veiga, J., Teyton, L. & Bendelac, A. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485–492 (2005). 41. Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank C. Murre (University of California San Diego) for discussions, reagents and mice; Y. Zhuang (Duke University) for Tcf12−/−, Tcf12f/f and Tcfe2af/f mouse lines; A. Bendelac (Howard Hughes Medical Institute) and M. Kronenberg (La Jolla Institute for Allergy and Immunology) for Vα14-Jα18 TCR–transgenic mice; A. Abbas (University of California San Francisco) for the constructs MSCV2.2–Bcl-xL–IRES–Thy-1.1 and MSCV2.2–empty–IRES–Thy-1.1; M. Kronenberg for advice; I. Ch'en for advice and assistance; and J. Hamerman, G. Barton, E. Zuniga and S. Hedrick and members of the Goldrath laboratory for critical review of the manuscript. Supported by the Cancer Research Institute, the Pew Charitable Trusts, the National Institutes of Health (AI067545 and AI072117 to A.W.G.), the Leukemia & Lymphoma Society (L.M.D.) and University of California San Diego undergraduate research scholarship program (J.K.F.).

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  1. Division of Biology, University of California San Diego, La Jolla, California, USA

    Louise M D'Cruz, Jamie Knell, Jessica K Fujimoto & Ananda W Goldrath

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  1. Louise M D'Cruz
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L.M.D. designed the study, did experiments, analyzed data and wrote the manuscript; J.K. and J.K.F. did experiments and analyzed data; and A.W.G. designed the study, analyzed data and wrote the manuscript.

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Correspondence to Ananda W Goldrath.

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D'Cruz, L., Knell, J., Fujimoto, J. et al. An essential role for the transcription factor HEB in thymocyte survival, Tcra rearrangement and the development of natural killer T cells. Nat Immunol 11, 240–249 (2010). https://doi.org/10.1038/ni.1845

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