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Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II–restricted cytotoxic T lymphocytes

Nature Immunology volume 14, pages 281–289 (2013)Cite this article

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Abstract

TCRαβ thymocytes differentiate into either CD8αβ+ cytotoxic T lymphocytes or CD4+ helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II–restricted CD4+ thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4+ T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4+ T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II–restricted CD4+ cytotoxic T lymphocytes.

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Figure 1: Some mature CD4+ T cells do not maintain ThPOK expression in the periphery.
Figure 2: Mature ThPOK− CD4+ T cells are the progeny of ThPOK-expressing thymocytes.
Figure 3: ThPOK− CD4+ effector cells lost ThPOK as mature cells in the periphery.
Figure 4: Activated CD4+ helper T cells that lose ThPOK expression differentiate into CTLs.
Figure 5: The Thpok silencer forms the switch that terminates Thpok expression in mature CD4+ T cells.
Figure 6: The ThPOK loss and reprogramming of CD4+ CTLs is an antigen-driven process in vivo.

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Acknowledgements

We thank A. Larange and I. Vicente-Suarez for discussions and critical reading of the manuscript; M. Cheroutre for contributions in conceiving of the project; Y. Wang-Zhu for preparing tetramers of the thymic leukemia antigen and breeding Rag1−/− mice; C. Kim and K. Van Gunst for cell sorting; D. Littman (New York University) for E8I-deficient mice; and D. Kappes (Fox Chase Cancer Center) for Thpok vectors. Supported by the US National Institutes of Health (R01 AI050265 and DP1 OD006433 to H.C.; F32 DK082249 to J.-W.S.; and P01 DK46763 to M.K. and H.C.), the Research Center for Allergy and Immunology (H.C. and I.T.), the Japan Society for the Promotion of Science (I.T.), Ter Meulen fund (F.v.W.) and the Crohn's & Colitis Foundation of America (D.M.). This is manuscript 1263 from the La Jolla Institute for Allergy and Immunology.

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  1. Daniel Mucida, Femke van Wijk, Ryo Shinnakasu, Yoshinori Naoe, Michael Docherty, Antoine Attinger, Peng Wang, Koji Atarashi, Yunji Park & Kenya Honda

    Present address: Present addresses: Laboratory of Mucosal Immunology, The Rockefeller University, New York, New York, USA (D.M.), Department of Pediatric Immunology, University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, The Netherlands (F.v.W.), RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan (R.S., K.A. and K.H.), Section of Immunology, Department of Mechanism of Aging, National Center for Geriatrics and Gerontology, Japan (Y.N.), Department of Gastroenterology, University of California San Diego Medical Center, San Diego, California, USA (M.D.), Merck-Serono, Versoix, Switzerland (A.A.), The Center for Nanomedicine, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China (P.W.) and Division of Integrative Bioscience and Biotechnology, Pohang University of Science and Technology, Pohang, Korea (Y.P.).,

  2. Daniel Mucida, Mohammad Mushtaq Husain, Sawako Muroi and Femke van Wijk: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Developmental Immunology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA

    Daniel Mucida, Mohammad Mushtaq Husain, Femke van Wijk, Ryo Shinnakasu, Yujun Huang, Florence Lambolez, Michael Docherty, Antoine Attinger, Jr-Wen Shui, Gisen Kim, Christopher J Lena, Yunji Park, Mitchell Kronenberg & Hilde Cheroutre

  2. Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan

    Sawako Muroi, Yoshinori Naoe, Chizuko Miyamoto & Ichiro Taniuchi

  3. Laboratory of Mucosal Immunology, The Rockefeller University, New York, New York, USA

    Bernardo Sgarbi Reis

  4. Institute of Immunology, Center for Physiology, Pathophysiology and Immunology, Medical University of Vienna, Vienna, Austria

    Shinya Sakaguchi & Wilfried Ellmeier

  5. Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA

    Peng Wang

  6. Department of Immunology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Koji Atarashi & Kenya Honda

  7. Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Toshinori Nakayama

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Contributions

H.C., I.T., M.K., D.M. and M.M.H. conceived of the project; M.M.H., D.M. and F.v.W. generated the phenotypic and functional data; I.T., S.M., Y.N. and C.M. generated the data on fate mapping and deletion of the Thpok silencer and did the ChIP assays; R.S. transfected cells; Y.H. provided the data on IL-7R-deficient mice; B.S.R., M.D. and A.A. generated the gene arrays; G.K., F.L. and C.J.L. transferred cells and analyzed mice; J.-W.S. and D.M. infected mice with citrobacter; K.A. and K.H. reconstituted germ-free mice; S.S. generated the data on the role of MAZR; Y.P. analyzed Myd88−/− mice; P.W., D.M., F.v.W., B.S.R. and H.C. analyzed the gene-array data; T.N. and W.E. provided expertise; M.K. provided conceptual advice and helped with data analysis and writing of the manuscript; I.T. and H.C. generated concepts, designed experiments, analyzed data and wrote the manuscript; and all authors contributed to the writing of the manuscript and provided advice.

Corresponding authors

Correspondence to Ichiro Taniuchi or Hilde Cheroutre.

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Mucida, D., Husain, M., Muroi, S. et al. Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II–restricted cytotoxic T lymphocytes. Nat Immunol 14, 281–289 (2013). https://doi.org/10.1038/ni.2523

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