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The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage

Nature Immunology volume 11, pages 435–441 (2010)Cite this article

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Abstract

Type I invariant NKT cells (iNKT cells) are a subset of αβ T cells characterized by the expression of an invariant α-chain variable region 14–α-chain joining region 18 (Vα14Jα18) T cell antigen receptor (TCR) α-chain. The iNKT cells derive from CD4+CD8+ double-positive (DP) thymocytes, and their generation requires a long half-life of DP thymocytes to allow Vα14-Jα18 rearrangements, expression of glycolipid-loaded CD1d on DP thymocytes, and signaling through the signaling-activation molecule SLAM–adaptor SAP pathway. Here we show that the transcription factor c-Myb has a central role in priming DP thymocytes to enter the iNKT lineage by simultaneously regulating CD1d expression, the half-life of DP cells and expression of SLAMF1, SLAMF6 and SAP.

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Figure 1: Lack of iNKT cells in Mybf/fCd4-Cre mice.
Figure 2: Cell-intrinsic defect in iNKT cell development in c-Myb-deficient mice.
Figure 3: Defects in secondary TCRα rearragements in c-Myb-deficient thymocytes.
Figure 4: Defect in the survival of c-Myb-deficient DP thymocytes.
Figure 5: Bcl-xL overexpression in c-Myb-deficient thymocytes restores survival and rearrangement but not iNKT cell development.
Figure 6: Partial 'rescue' of the iNKT cell defect in c-Myb-deficient mice by a rearranged Vα14Jα18 TCR transgene.
Figure 7: Lower expression of SLAMF1 and SLAMF6 in c-Myb-deficient mice.
Figure 8: DP thymocytes that lack c-Myb are unable to support the development of CD1d deficient iNKT cells.

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Acknowledgements

We thank A. Bendelac (Howard Hughes Medical Institute) for the Vα14-transgenic mice; A. Veillette (Clinical Research Institute, Montreal) for the antibody to SAP; X.-H. Sun (Oklahoma Medical Research Foundation) for the Mig-RORγt vector; M. Lang (University of Oklahoma Health Science Center) for CD1d-deficient- and Jα18-deficient- bone marrow; the National Institutes of Health Tetramer Facility for the CD1d-PBS57 tetramer; and S. Kovats for discussions. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (AI059302 to J.A.-I.), the American Heart Association (0855002F to J.A.-I.), the National Cancer Institute of the National Institutes of Health (CA85842 to T.B.P.) and the Robert R. Wagner Fellowship Fund (J.Y.).

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Authors and Affiliations

  1. Immunobiology and Cancer Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA

    Taishan Hu, Amie Simmons & Jose Alberola-Ila

  2. Department of Microbiology, University of Virginia, Charlottesville, Virginia, USA

    Joan Yuan & Timothy P Bender

  3. Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Jose Alberola-Ila

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T.H. designed the study, did experiments, analyzed data and wrote the manuscript; A.S. did experiments; J.Y and T.P.B. provided experimental mice, data and discussions; and J.A.-I. designed the study, did experiments, analyzed data and wrote the manuscript.

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Correspondence to Jose Alberola-Ila.

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Hu, T., Simmons, A., Yuan, J. et al. The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage. Nat Immunol 11, 435–441 (2010). https://doi.org/10.1038/ni.1865

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