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The transcriptional landscape of αβ T cell differentiation

Nature Immunology volume 14, pages 619–632 (2013)Cite this article

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Abstract

The differentiation of αβT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4+CD8+ stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4+ or CD8+ lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation.

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Figure 1: 'Birds-eye' view of transcriptome changes during the course of T cell differentiation.
Figure 2: Dynamics of gene expression during early T cell differentiation.
Figure 3: Transcriptional footprint of β-selection.
Figure 4: Transcriptional shutdown in small DP thymocytes.
Figure 5: Reactivation of housekeeping activities after positive selection.
Figure 6: Transcriptional and functional 'footprints' of clonal deletion in CD69+ DP thymocytes.
Figure 7: Acquisition of CD4+ and CD8+ transcriptional identities during thymocyte differentiation.
Figure 8: Definition of CD4+ and CD8+ transcriptional identities.

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Gene Expression Omnibus

Change history

  • 13 May 2013

    In the version of this article initially published online, the eighth and ninth author names were incorrect. Those should be Matthew H. Spitzer and Garry P. Nolan. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank K. Hattori, A. Ortiz-Lopez and N. Asinovski for technical assistance with mice and antibodies; J. Moore and A. Kressler for flow cytometry; and C. Laplace for assistance with figure preparation. Supported by the US National Institutes of Health (AI072073), the Human Frontier Science Program (HFSP-LT000096 to M.M.), the National Health and Medical Research Council (637353 to D.G.) and the Australian Research Council (LP110201169 to, T.H.).

Author information

Author notes

  1. Michael Mingueneau, Taras Kreslavsky, Daniel Gray, Tracy Heng, Nidhi Malhotra, Katelyn Sylvia and Joonsoo Kang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA

    Michael Mingueneau, Richard Cruse, Jeffrey Ericson, Diane Mathis, Christophe Benoist, Katherine Rothamel & Adriana Ortiz-Lopez

  2. Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Taras Kreslavsky, Koichi Kobayashi & Harald von Boehmer

  3. Department of Medical Biology, University of Melbourne, Parkville, Australia

    Daniel Gray

  4. Molecular Genetics of Cancer Division and Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Daniel Gray

  5. Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

    Tracy Heng

  6. Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, California, USA

    Sean Bendall, Matthew H Spitzer & Garry P Nolan

  7. Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College Station, Texas, USA

    Koichi Kobayashi

  8. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA

    Adam J Best, Jamie Knell & Ananda Goldrath

  9. Computer Science Department, Stanford University, Stanford, California, USA

    Vladimir Jojic & Daphne Koller

  10. Broad Institute and Department of Biology, MIT, Cambridge, Massachusetts, USA

    Tal Shay & Aviv Regev

  11. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Nadia Cohen, Patrick Brennan & Michael Brenner

  12. Joslin Diabetes Center, Boston, Massachusetts, USA

    Francis Kim, Tata Nageswara Rao & Amy Wagers

  13. Department of Microbiology & Immunology, University of California San Francisco, San Francisco, California, USA

    Natalie A Bezman, Joseph C Sun, Gundula Min-Oo, Charlie C Kim & Lewis L Lanier

  14. Icahn Medical Institute, Mount Sinai Hospital, New York, New York, USA

    Jennifer Miller, Brian Brown, Miriam Merad, Emmanuel L Gautier, Claudia Jakubzick & Gwendalyn J Randolph

  15. Department of Pathology & Immunology, Washington University, St. Louis, Missouri, USA

    Emmanuel L Gautier & Gwendalyn J Randolph

  16. Department of Medicine, Boston University, Boston, Massachusetts, USA

    Paul Monach

  17. Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    David A Blair & Michael L Dustin

  18. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA

    Susan A Shinton & Richard R Hardy

  19. Computer Science Department, Brown University, Providence, Rhode Island, USA

    David Laidlaw

  20. Department of Biomedical Engineering, Howard Hughes Medical Institute, Boston University, Boston, Massachusetts, USA

    Jim Collins

  21. Program in Molecular Medicine, Children's Hospital, Boston, Massachusetts, USA

    Roi Gazit & Derrick J Rossi

  22. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA

    Nidhi Malhotra, Katelyn Sylvia & Joonsoo Kang

  23. Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA

    Anne Fletcher, Kutlu Elpek, Angelique Bellemare-Pelletier, Deepali Malhotra & Shannon Turley

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  1. Michael Mingueneau
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  2. Taras Kreslavsky
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  4. Tracy Heng
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  6. Jeffrey Ericson
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  8. Matthew H Spitzer
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  9. Garry P Nolan
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  10. Koichi Kobayashi
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  11. Harald von Boehmer
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  13. Christophe Benoist
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Consortia

the Immunological Genome Consortium

  • Adam J Best
  • , Jamie Knell
  • , Ananda Goldrath
  • , Vladimir Jojic
  • , Daphne Koller
  • , Tal Shay
  • , Aviv Regev
  • , Nadia Cohen
  • , Patrick Brennan
  • , Michael Brenner
  • , Francis Kim
  • , Tata Nageswara Rao
  • , Amy Wagers
  • , Tracy Heng
  • , Jeffrey Ericson
  • , Katherine Rothamel
  • , Adriana Ortiz-Lopez
  • , Diane Mathis
  • , Christophe Benoist
  • , Natalie A Bezman
  • , Joseph C Sun
  • , Gundula Min-Oo
  • , Charlie C Kim
  • , Lewis L Lanier
  • , Jennifer Miller
  • , Brian Brown
  • , Miriam Merad
  • , Emmanuel L Gautier
  • , Claudia Jakubzick
  • , Gwendalyn J Randolph
  • , Paul Monach
  • , David A Blair
  • , Michael L Dustin
  • , Susan A Shinton
  • , Richard R Hardy
  • , David Laidlaw
  • , Jim Collins
  • , Roi Gazit
  • , Derrick J Rossi
  • , Nidhi Malhotra
  • , Katelyn Sylvia
  • , Joonsoo Kang
  • , Taras Kreslavsky
  • , Anne Fletcher
  • , Kutlu Elpek
  • , Angelique Bellemare-Pelletier
  • , Deepali Malhotra
  •  & Shannon Turley

Contributions

M.M., T.K., D.G. and T.H. designed, did and analyzed some of the experiments and wrote the manuscript; R.C. and J.E. helped with microarray data analysis; S.B. and M.H.S. designed, did and analyzed some of the experiments; G.P.N. and K.K. and H.v.B. contributed resources and assisted with data analysis; and D.M. and C.B. directed the study, analyzed and interpreted results and wrote the manuscript.

Corresponding authors

Correspondence to Diane Mathis or Christophe Benoist.

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The authors declare no competing financial interests.

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A full list of members and affiliations appears at the end of the paper.

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Mingueneau, M., Kreslavsky, T., Gray, D. et al. The transcriptional landscape of αβ T cell differentiation. Nat Immunol 14, 619–632 (2013). https://doi.org/10.1038/ni.2590

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