The transcriptional landscape of αβ T cell differentiation

Michael Mingueneau, Taras Kreslavsky, Daniel Gray, Tracy Heng, Richard Cruse, Jeffrey Ericson, Sean Bendall, Matthew H. Spitzer, Garry P. Nolan, Koichi Kobayashi, Harald Von Boehmer, Diane Mathis, Christophe Benoist, Adam J. Best, Jamie Knell, Ananda Goldrath, Daphne Koller, Tal Shay, Aviv Regev, Nadia CohenPatrick Brennan, Michael Brenner, Francis Kim, Tata Nageswara Rao, Amy Wagers, Katherine Rothamel, Adriana Ortiz-Lopez, 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, Anne Fletcher, Kutlu Elpek, Angelique Bellemare-Pelletier, Deepali Malhotra, Shannon Turley

Research output: Contribution to journalArticle

148 Scopus citations

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.

Original languageEnglish
Pages (from-to)619-632
Number of pages14
JournalNature immunology
Volume14
Issue number6
DOIs
StatePublished - Jun 2013

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    Mingueneau, M., Kreslavsky, T., Gray, D., Heng, T., Cruse, R., Ericson, J., Bendall, S., Spitzer, M. H., Nolan, G. P., Kobayashi, K., Von Boehmer, H., Mathis, D., Benoist, C., Best, A. J., Knell, J., Goldrath, A., Koller, D., Shay, T., Regev, A., ... Turley, S. (2013). The transcriptional landscape of αβ T cell differentiation. Nature immunology, 14(6), 619-632. https://doi.org/10.1038/ni.2590