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Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4+CD8+ thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16, which encodes the NKT lineage-specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb, which encodes the interleukin 2 (IL-2) receptor ?-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to 'instruct' a thymic lineage. [ABSTRACT FROM AUTHOR]

Summary The precise impact of thymic positive and negative selection on the T cell receptor (TCR) repertoire remains controversial. Here, we used unbiased, high-throughput cloning and retroviral expression of individual pre-selection TCRs to provide a direct assessment of these processes at the clonal level in vivo. We found that 15% of random TCRs induced signaling and directed positive (7.5%) or negative (7.5%) selection, depending on strength of signal, whereas the remaining 85% failed to induce signaling or selection. Most negatively selected TCRs exhibited promiscuous crossreactivity toward multiple other major histocompatibility complex (MHC) haplotypes. In contrast, TCRs that were positively selected or non-selected were minimally crossreactive. Negative selection of crossreactive TCRs led to clonal deletion but also recycling into intestinal CD4 − CD8β − intraepithelial lymphocytes (iIELs). Thus, broadly crossreactive TCRs arise at low frequency in the pre-selection repertoire but constitute the primary drivers of thymic negative selection and iIEL lineage differentiation. [ABSTRACT FROM AUTHOR]

The developmental pathway of intestinal TCRαβ+CD4- CD8β- intraepithelial lymphocytes (unconventional iIELs) has remained elusive. Bendelac and colleagues demonstrate that expression of unconventional iIEL TCRs in thymocytes causes negative selection and that unconventional iIELs are derived from rare escapees of cortical negative selection. [ABSTRACT FROM AUTHOR]

Highlights: [•] We reported Egr2 as a central transcriptional regulator of T cell anergy induction. [•] Microarray and ChIP-Seq analyses were conducted to investigate Egr2 transcriptome. [•] 49 new targets were identified to be directly regulated by Egr2 in anergic cells. [•] Egr2 regulates several cell surface and secreted molecules in anergic cells. [ABSTRACT FROM AUTHOR]