Chromatin condensation via the condensin II complex is required for peripheral T-cell quiescence.

This paper reports the remarkable finding that a component of the condensin complex is involved in preventing transcription factor access to target gene loci in quiescent T cells that are naive to antigen.

The authors find that peripheral T cells that have not engaged antigen can still respond to cytokines by translocating the appropriate transcription factors to the nucleus, and they ask why these cells then do not respond by proliferating inappropriately. They show that extreme chromatin compaction prevents transcription factors accessing their gene targets in these cells. T cells that do engage with antigen lose this chromatin compaction, allowing for the activation of the transcriptional program leading to clonal T cell proliferation. Searching through the immunological phenotypes of mutant mice, the authors demonstrate that a component of the condensin complex is required to maintain the compact inaccessible chromatin state of naive T cells. In addition to mitotic functions, condensins have been shown to function in dosage compensation in worms and transvection in flies. The paper adds gene silencing in the mammalian immune system to this list.

This is the first study to show that chromatin condensation generally occurs during T lymphocyte development in the thymus, which could explain the drastically reduced global levels of transcription observed in mostly quiescent, peripheral naive T lymphocytes. However, upon encountering their cognate antigenic target, these cells become activated and undergo proliferation, a behavior that is associated with chromatin decondensation, and may, thus, provide an essential control to ensure that only antigen-specific T cells will expand.

The authors notably showed that rapid chromatin condensation takes place during thymocyte transition from the so-called CD4/CD8 double-negative (DN) to CD4/CD8 double-positive (DP) cell stage, and depends on the function of the condensin II complex, and, in particular, one subunit in this complex: kleisin-beta. Intriguingly, this process is apparently not a function of CpG dinucleotide methylation and does not associate with global histone epigenetic modifications, including mono-, di- and tri-methylated histone H3K4, tri-methylated histone H3K9/27 and acetylated histone H3.

This report is of interest as it indicates that chromatin condensation is a key regulator of T cell responsiveness.

Naïve T cells, that have successfully navigated the process of thymic selection, exit into the periphery in a quiescent state. Their full activation is dependent upon antigenic signals received via T cell receptor (TCR) engagement and is assisted by the presence of cytokines such as interleukin (IL)-2, as well as by the engagement of costimulatory molecules. This tight regulation, and exquisite dependence on antigenic stimulation, prevents the induction of illegitimate responses.

This report investigates why naïve T cells are relatively refractory to IL-2 stimulation in the absence of TCR-derived signals. The findings indicate that chromatin condensation in naïve T cells controls their ability to become activated. The condensed state is established during thymic selection and is maintained by the peripheral naïve T cells. Consequently, the condensed chromatin occludes access of the transcription factor Stat-5 to IL-2-regulated genes. Antigen activation results in global decondensation, allowing Stat-5 engagement with promoter sites, thus permitting the activation of IL-2-regulated genes.