Most developing thymocytes are destined to die; so what enables them to overcome the odds, and survive and mature into functional T cells? Reporting in The Journal of Experimental Medicine, two groups have identified an important role for survivin — a member of the inhibitor of apoptosis protein (IAP) family — in T-cell development.

T-cell development in the thymus involves a series of distinct stages that can be defined by the expression of cell-surface markers. Early T cells are CD4−CD8− double negative (DN) and can be further subdivided into DN1, DN2, DN3 and DN4 stages based on their expression of CD25 and CD44. Productive rearrangement of the T-cell receptor (TCR) β-chain locus occurs during the DN3 to DN4 transition and leads to expression of the pre-TCR. Only cells that express a functional pre-TCR undergo marked proliferation and differentiate into CD4+CD8+ double-positive (DP) cells. However, most DP cells die through negative selection or neglect because their TCRs have too high or too low affinity for peptide–MHC complexes. Those that mature successfully migrate to the periphery as functional CD4+CD8− or CD4−CD8+ single-positive T cells.

Survivin is expressed by highly proliferating cells and has previously been implicated in cell-cycle progression. Yet, despite being a member of the IAP family, its role in apoptosis is controversial. Both groups set out to study the role of survivin in the control of proliferation and apoptosis in T-cell development. Because survivin deficiency is embryonic lethal, both groups used a conditional deletion strategy to specifically knockout the gene encoding survivin in developing thymocytes. Zheng Xing et al. generated two T-cell-specific survivin-deficient mouse lines with the deletion occurring at different developmental stages. Lck-survivin mice, in which survivin deletion occurs by the DN3 stage, had defective thymocyte development as a result of arrested cell proliferation. However, when survivin was deleted later at the DN4 stage (CD4-survivin mice), the early stages of thymocyte development were normal, but peripheral T cells were immature and markedly reduced in numbers owing to problems with T-cell homeostatic proliferation. Together, these observations indicate an important role for survivin at early and late stages of T-cell development.

Tak Mak and colleagues also found that thymocyte development was blocked at the DN3 to DN4 transition in Lck-survivin mice. They observed increased apoptosis but, in agreement with Xing et al., apoptosis to external stimuli proceeds normally in survivin-deficient cells. In response to proliferative stimuli, the absence of survivin triggered cell-cycle arrest, defective spindle formation and cell death of proliferating thymocytes. Although loss of survivin induced expression of pro-apoptotic p53, neither p53 loss nor overexpression of anti-apoptotic Bcl-2 could restore the development of survivin-deficient DN3 thymocytes, indicating that the protective function of survivin is independent of p53 and Bcl-2. The authors also observed severe defects in chromosomal segregation and cytokinesis in survivin-deficient cells and suggest that the main role of survivin is in controlling mitosis progression, and that cell death was secondary to these defects.

Both papers highlight an important role for survivin in enabling thymocytes to progress from the DN to DP phenotype and show that survivin does not have a primary role in apoptosis. Further experiments are required to understand how survivin-mediated T-cell homeostasis is regulated.