The appearance of grey hairs is just one sign that a person is getting older. Changes within our immune system also occur as we age. The thymus — the site of T-cell development — shrinks or involutes from adolescence onwards. Until now, the molecular signals involved in the maintenance of the thymus have been unclear. Work by Sano and colleagues in Immunity now shows an essential role for signal transducer and activator of transcription 3 (Stat3) in these processes.

Interactions between thymic stromal cells and lymphoid cells are vital for the formation and maintenance of thymic structure. Stat3, a transcriptional regulator involved in growth-factor signalling, might be important in these processes. As Stat3−/− mice die mid-gestation, the authors used Cre/loxP technology to investigate the role of Stat3 in the maintenance of thymic architecture. They crossed Stat3 floxed mice with transgenics that expressed Cre recombinase under the control of the keratin 5 (K5) promoter, so that Stat3 was exclusively deleted in stratified epithelial cells. This is the first time this technique has been used to successfully delete a gene from thymic epithelial cells (TECs) without affecting the genomes of the thymocytes. At birth thymocyte development was normal in these mice, but from adolescence onwards the numbers of thymocytes in the Stat3−/− mice decreased significantly in comparison with wild-type littermates. This thymic hypoplasia worsened with age, as did the observed changes in cortical TEC architecture.

Stat3 activates the expression of anti-apoptotic proteins, so the authors next asked whether the age-dependent thymic hypoplasia resulted from increased apoptosis. They found more apoptotic thymocytes in the thymi of Stat3−/− mice than in wild-type mice, and destruction of the thymic architecture was evident. When thymcytes were removed from the Stat3 mutant mice and exposed in vitro to apoptotic stimuli, the cells were no more sensitive to apoptosis that thymocytes from wild-type mice. So, the increased sensitivity of these cells is not due to an intrinsic defect, but rather due to a failure of the Stat3−/− TECs to protect them from apoptotic stimuli.

In conclusion, these results show that Stat3 is vital in the maintenance of thymic architecture and for the survival of thymocytes. As far as the thymus goes then, Stat3 is a protein you need if you want to maintain control of the ageing process.