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.
Bibliographical noteFunding Information:
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.).