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Both intermittent interleukin-7 (IL-7)-mediated signalling and homeostatic T cell receptor (TCR) engagement with self ligands presented on MHC class I molecules are necessary for the survival of naive CD8+ T cells, but the reasons for this are unclear. Kimura et al. now show that naive CD8+ T cells need regular breaks from IL-7, as prolonged exposure to this cytokine promotes their death.

CD8+ T cells need regular breaks from IL-7, as prolonged exposure to this cytokine promotes their death

IL-7 is produced by stromal cells in the thymus and periphery and promotes CD8+ T cell survival by upregulating the pro-survival molecules BCL-2 and MCL1. In response to IL-7, CD8+ T cells downregulate their expression of the IL-7 receptor (IL-7R); they require homeostatic TCR engagement to re-express IL-7R and respond to subsequent IL-7 signals. To understand why this intermittent loss of IL-7R expression is necessary, Kimura et al. generated transgenic mice in which naive CD8+ T cells are refractory to IL-7R downregulation and continue to respond to IL-7 (termed 7RTg mice). They then assessed whether continuous IL-7R signalling can substitute for TCR-mediated survival signals using a model of lymphopenia in MHC-competent mice and MHC class I-deficient mice.

As expected, wild-type CD8+ T cells proliferated and survived when transferred to lymphopenic mice, and both processes were MHC class I dependent. By contrast, 7RTg CD8+ T cells underwent extensive proliferation in MHC class I-deficient lymphopenic mice, but they could not subsequently persist in these mice. Further experiments showed that prolonged IL-7R signalling caused 7RTg CD8+ T cells to proliferate, convert to an activated phenotype, upregulate expression of interferon-γ (IFNγ) and undergo apoptosis. On the other hand, intermittent IL-7R signalling maintained 7RTg CD8+ T cells as viable, quiescent cells.

So, given that intermittent IL-7R signalling promotes the survival of CD8+ T cells, why does prolonged signalling lead to their death? The authors found that continuous IL-7R signalling did not reduce the expression of pro-survival molecules in CD8+ T cells, but led to the upregulation of the pro-apoptotic molecules FAS (also known as CD95), FASL (also known as CD95L), BIM and active caspase 3. Deficiency of IFNγ or its receptor inhibited caspase 3 activation and apoptosis in CD8+ T cells, suggesting that the upregulation of IFNγ in response to prolonged IL-7R signalling promotes CD8+ T cell death. In further support of this, CD8+ T cells in 7RTg mice showed exponential growth in both in vitro and in vivo systems when IFNγ-mediated signalling was blocked.

Finally, the authors found that weaker homeostatic TCR engagements lead to uninterrupted IL-7R signalling in CD8+ T cells and higher expression levels of IFNγ and FASL. By contrast, stronger homeostatic TCR engagements induce interrupted IL-7R signalling in CD8+ T cells and lower levels of IFNγ and FASL expression. Together, these data show that interruptions in IL-7 signalling are crucial for CD8+ T cell homeostasis. Kimura et al. suggest that this may serve as a 'quality-control' mechanism to eliminate T cells that lack specificity or affinity for MHC class I-restricted antigens.