The trimethylation of histone H3 lysine 27 (H3K27Me3) contributes to gene repression, notably through recruitment of Polycomb complexes, and has long been considered essential to maintain cell ...identity. Whereas H3K27Me3 was thought to be stable and not catalytically reversible, the discovery of the Utx and Jmjd3 demethylases changed this notion, raising new questions on the role of these enzymes in gene expression and cell differentiation. Recent studies have demonstrated critical roles for Utx and Jmjd3 in the development and function of immune cells, and revealed both demethylase and demethylase-independent activities of these enzymes. I review these finding here, and discuss the current understanding of the mechanisms that underlie the broad, yet highly cell- and gene-specific, impact of these enzymes in vivo.
Decision checkpoints in the thymus Bosselut, Rémy; Carpenter, Andrea C
Nature immunology,
08/2010, Letnik:
11, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The development of T cells in the thymus involves several differentiation and proliferation events, during which hematopoietic precursors give rise to T cells ready to respond to antigen stimulation ...and undergo effector differentiation. This review addresses signaling and transcriptional checkpoints that control the intrathymic journey of T cell precursors. We focus on the divergence of alphabeta and gammadelta lineage cells and the elaboration of the alphabeta T cell repertoire, with special emphasis on the emergence of transcriptional programs that direct lineage decisions.
In addition to transcription factor binding, the dynamics of DNA modifications (methylation) and chromatin structure are essential contributors to the control of transcription in eukaryotes. Research ...in the past few years has emphasized the importance of histone H3 methylation at lysine 27 for lineage specific gene repression, demonstrated that deposition of this mark at specific genes is subject to differentiation-induced changes during development, and identified enzymatic activities, methyl transferases and demethylases, that control these changes. The present review discusses the importance of these mechanisms during intrathymic αβ T cell selection and late differentiation.
Tissue-resident memory T cells (Trm), which typically do not enter the blood or lymphatic circulation at steady-state, are considered crucial for controlling pathogen entry at skin and mucosal ...barriers. Two recent studies (Fonseca et al. and Crowl et al.) shed light on the mechanisms of Trm cell differentiation.
T cell immunity requires the long-term survival of T cells that are capable of recognizing self antigens but are not overtly autoreactive. How this balance is achieved remains incompletely ...understood. Here we identify a homeostatic mechanism that transcriptionally tailors CD8 coreceptor expression in individual CD8+ T cells to the self-specificity of their clonotypic T cell receptor (TCR). 'Coreceptor tuning' results from interplay between cytokine and TCR signals, such that signals from interleukin 7 and other common gamma-chain cytokines transcriptionally increase CD8 expression and thereby promote TCR engagement of self ligands, whereas TCR signals impair common gamma-chain cytokine signaling and thereby decrease CD8 expression. This dynamic interplay induces individual CD8+ T cells to express CD8 in quantities appropriate for the self-specificity of their TCR, promoting the engagement of self ligands, yet avoiding autoreactivity.
The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the ...role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8
T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs
. However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made
, the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8α, Granzyme B and perforin
. Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools.
Highlights ► An enhancer active in the thymus imprints epigenetic memory within the Cd4 locus. ► A Thpok-Runx3 regulatory loop controls CD4–CD8 lineage commitment and contributes to maintain lineage ...identity. ► Transcription factors Mazr and Runx1 contribute to the Thpok-Runx3 commitment loop. ► Newly indentified transcription factors promote Thpok and Runx3 expression and CD4 or CD8 lineage specification.
CD8⁺ T cells are preprogrammed for cytotoxic differentiation in the thymus as they acquire expression of the transcription factor Runx3. However, a subset of effector CD8⁺ T cells (Tc17) produce ...IL-17 and fail to express cytotoxic genes. Here, we show that the transcription factors directing IL-17 production, STAT3 and RORγt, inhibit cytotoxicity despite persistent Runx3 expression. Cytotoxic gene repression did not require the transcription factor Thpok, which in CD4⁺ T cells restrains Runx3 functions and cytotoxicity; and STAT3 restrained cytotoxic gene expression in CD8⁺ T cells responding to viral infection in vivo. STAT3-induced RORγt represses cytotoxic genes by inhibiting the functions but not the expression of the “cytotoxic” transcription factors T-bet and Eomesodermin. Thus, the transcriptional circuitry directing IL-17 expression inhibits cytotoxic functions. However, by allowing expression of activators of the cytotoxic program, this inhibitory mechanism contributes to the instability of IL-17–producing T cells.
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