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Mouse Hobit is a homolog of the transcriptional repressor Blimp-1 that regulates NKT cell effector differentiation

Nature Immunology volume 13, pages 864–871 (2012)Cite this article

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Abstract

The transcriptional repressor Blimp-1 mediates the terminal differentiation of many cell types, including T cells. Here we identified Hobit (Znf683) as a previously unrecognized homolog of Blimp-1 that was specifically expressed in mouse natural killer T cells (NKT cells). Through studies of Hobit-deficient mice, we found that Hobit was essential for the formation of mature thymic NKT cells. In the periphery, Hobit repressed the accumulation of interferon-γ (IFN-γ)-producing NK1.1lo NKT cells at steady state. After antigenic stimulation, Hobit repressed IFN-γ expression, whereas after innate stimulation, Hobit induced granzyme B expression. Thus, reminiscent of the function of Blimp-1 in other lymphocytes, Hobit controlled the maintenance of quiescent, fully differentiated NKT cells and regulated their immediate effector functions.

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Figure 1: NKT cells specifically express the Blimp-1 homolog Hobit.
Figure 2: Thymic mature NKT cells are dependent on Hobit.
Figure 3: Ly49C/I+ NKT cells require Hobit to develop from NK1.1lo and NK1.1hi precursor cells.
Figure 4: Hobit controls the NK1.1lo population of peripheral NKT cells.
Figure 5: Hobit impairs NKT cell population expansion not driven by proliferation.
Figure 6: Hobit modulates IFN-γ production after antigen-dependent activation of NKT cells.
Figure 7: NKT cells produce granzyme B in a Hobit-dependent manner after antigen-independent activation.
Figure 8: Hobit regulates the production of granzyme B and IFN-γ in NKT cells during infection with MCMV.

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Acknowledgements

We thank L. Boon (Bioceros) for antibodies; J.C. Zúñiga-Pflücker (Sunnybrook Research Institute) for OP9-DL1 cells; the staff of the animal facility of the Academic Medical Center for animal care; A. de Bruin for technical assistance; B. Hooibrink, E. Mul and F. van Alphen for cell sorting; D. Edo-Matas for help with phylogenetic analysis; and A. Kallies for critical reading of the manuscript. Supported by The Netherlands Organization of Scientific Research (M.A.N. and R.A.W.v.L.) and the Landsteiner Foundation for Blood Transfusion Research (N.A.M.K.).

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Author notes

  1. Klaas P J M van Gisbergen

    Present address: Present address: Division of Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.,

  2. Natasja A M Kragten and Kirsten M L Hertoghs: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematopoiesis, Sanquin Research at CLB and Landsteiner Laboratory, Amsterdam, The Netherlands

    Klaas P J M van Gisbergen, Natasja A M Kragten, Martijn A Nolte & Rene A W van Lier

  2. Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands

    Klaas P J M van Gisbergen, Natasja A M Kragten, Kirsten M L Hertoghs, Jörg Hamann, Martijn A Nolte & Rene A W van Lier

  3. Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia

    Felix M Wensveen & Stipan Jonjic

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Contributions

K.P.J.M.v.G., N.A.M.K., K.M.L.H. and F.M.W. did experiments; K.P.J.M.v.G., S.J., J.H., M.A.N. and R.A.W.v.L. designed experiments; and K.P.J.M.v.G., M.A.N. and R.A.W.v.L. wrote the manuscript.

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Correspondence to Klaas P J M van Gisbergen.

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van Gisbergen, K., Kragten, N., Hertoghs, K. et al. Mouse Hobit is a homolog of the transcriptional repressor Blimp-1 that regulates NKT cell effector differentiation. Nat Immunol 13, 864–871 (2012). https://doi.org/10.1038/ni.2393

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