The transcriptional landscape of αβ T cell differentiation

Abstract

αβT cell differentiation from thymic precursors is a complex process, explored here with the breadth of ImmGen expression datasets, analyzing how differentiation of thymic precursors gives rise to transcriptomes. After surprisingly gradual changes though early T commitment, transit through the CD4+CD8+ stage involves a shutdown or rare breadth, and correlating tightly with MYC. MHC-driven selection promotes a large-scale transcriptional reactivation. We identify distinct signatures that mark cells destined for positive selection versus apoptotic deletion. Differential expression of surprisingly few genes accompany CD4 or CD8 commitment, a similarity that carries through to peripheral T cells and their activation, revealed by mass cytometry phosphoproteomics. The novel transcripts identified as candidate mediators of key transitions help define the “known unknown” of thymocyte differentiation.

Distinct phases in the positive selection of CD8+T cells distinguished by intrathymic migration and T-cell receptor signaling patterns

“…High motility is a consistent feature of SP thymocytes in the medulla (6,25,34,35) and mature T cells in lymph nodes (36), implying that increased motility reflects long-lasting changes in the cellular machinery that controls migration, rather than a short-term response to a chemokine gradient. Consistent with this notion, gene-expression studies of pre-and postselection DP thymocytes revealed induction of numerous genes that may play a role in regulating cell adhesion, metabolism, and the cytoskeleton (37)(38)(39).…”

CD11b+Ly6G−myeloid cells mediate mechanical inflammatory pain hypersensitivity

“…Transcriptional expression profiling of FACS-purified CD11b + Ly6G − Ly6C hi , Ly6C med , and Ly6C low cells isolated from the hind paw 24 h after the incisional wound, a time point of significant mechanical hypersensitivity, was carried out by microarray analysis to obtain mechanistic insight into their functional and activation states. A total of 8,169 transcripts remained after filtering out transcripts with low expression (39); the transcript with the highest variability among the three subsets of cells was Ly6C2 (σ = 2,318.2). The 50 most variable transcripts across these subsets were identified and ranked by average expression (Fig.…”

“…The microarray data has been deposited in the Gene Expression Omnibus database under accession number GSE73667. Transcripts were filtered for mean expression values >100 in any one population (39) and sorted by variability across the three populations of cells. Heat maps were generated by using the GenePattern platform (Broad Institute).…”

Transcription Factor 7 Limits Regulatory T Cell Generation in the Thymus

“…Recently, a Tcf7-Lef1 coregulated cluster of genes was described by the Immunological Genome Consortium (41). We compared this Tcf7-Lef1 coregulated cluster with our proteomics data and identified 19 members in our data set (Fig.…”