Controlling T cell proliferation

A central feature of cell-mediated immunity is clonal expansion of specific activated lymphocytes in response to cytokines. The mechanisms that restrict expansion solely to activated T cells that have bound their cognate antigen are incompletely understood. Now an article published in this fortnight’s edition of EMBO has revealed one mechanism of restriction which requires chromatin compaction.

After TCR rearrangement and selection in the thymus, naïve T-cells are released into the periphery of the body. These naïve T-cells cease to proliferate until they bind to their cognate antigen, which renders the T cell sensitive to cytokines such as IL-2 leading to proliferation and antigen dependent maturation of the cells. Activation of the IL-2 receptor triggers the phosphylation and nuclear translocation of the Stat5 transcription factor which drives this process. In the absence of antigen binding, however, the presence of IL-2 in the surrounding environment does not trigger cellular expansion. How do these quiescent T-cells ignore this surrounding IL-2 was previously unclear and was the question addressed by Rawlings et al. They show that in the absence of TCR activation, T cells still bind IL-2 triggering the translocation of Stat5 to the nucleus. However they found that despite its nuclear localisation Stat5 was unable to bind to the promoters of its target genes explaining why proliferation did not occur in these cells.

A common mechanism for blocking the access of transcription factors to target promoters is via chromatin remodelling. The authors, in this article provide evidence that the nuclei of naïve T-cells are made up primarily of condensed chromatin, which changes to a more open form upon activation of the TCR but not IL-2 treatment alone. The condensed nature of the chromatin and not DNA methylation or histone modification within the promoter region was found to be the cause of resistance to IL-2 signalling.

Using the nessy mouse model the authors reveal a novel role for the chromosome compaction complex condensin. Condensin is a pentameric Structural Maintenance of Chromosome (SMC) complex shown previously to be required for mitotic functions, DNA repair and the regulation of transcription. Now it appears condensin has a specialised role in maintaining quiescence in the immune system. The exact mechanism of how condensin is targeted and controlled by TCR activation remain to be revealed.



Rawlings et al (2011) Chromatin condensation via the condensing II complex is required for peripheral T cell quiescence. EMBO J 3O:263-276

Fuente: British Society for Immunology