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Intermittent IL-7 Signaling Essential for T cell Homeostasis

Image displays effects of presence and absence of homeostatic TCR signaling on CD8 T cells
Homeostatic TCR signaling driven by self ligands intermittently interrupts IL-7 signaling, which provides survival signals to naïve CD8 T cells. In contrast, absent homeostatic TCR signaling allows IL-7 signaling to be continuous, which induces IFNg production and triggers Cytokine Induced Cell Death (CICD)

In order for the immune system to mount an appropriate response to foreign antigens throughout a person’s life, the body must maintain a sufficient population of circulating mature, naïve T cells, a process known as T cell homeostasis. Previous studies revealed that this process depends upon signaling from the cytokine interleukin-7 (IL-7) as well as from the T cell antigen receptor (TCR). Intriguingly, signals from each pathway affect the other and lead to their alternating activation: IL-7 binding to its receptor leads to increasing expression of the TCR co-receptor CD8; sufficient CD8 expression allows TCRs to signal when bound to self-ligands, blocking IL-7 signaling; suppressed IL-7 signals lead to down-regulation of CD8 and ligand disengagement, which allows T cells to again respond to IL-7. Alfred Singer, M.D., and his colleagues in CCR’s Experimental Immunology Branch set out to understand how this intricate pathway promotes T cell survival.

The researchers first investigated what would happen if T cells received continuous IL-7 signaling. They generated a model of constitutive expression of the IL-7 receptor (IL-7R) by introducing the gene for the alpha subunit (IL-7Rα), under the control of a T cell specific, IL-7 insensitive promoter, into mice lacking the IL-7R and called this strain 7RTg. The scientists injected T cells from normal mice or 7RTg mice into two additional mouse strains, one sufficient in TCR self-ligands and one deficient. After 14 days the normal T cells proliferated in the sufficient animals because they received TCR signaling but failed to grow or survive in the deficient animals. The 7RTg T cells, however, proliferated in both the sufficient and deficient animals, but fewer cells were collected from the deficient animals, suggesting that continuous IL-7 signaling was capable of promoting cell growth, but not survival in the absence of TCR signaling. These results were surprising since IL-7 is thought to be a pro-survival cytokine.

To further elucidate the molecular details of this pathway, the researchers cultured the 7RTg T cells in IL-7. Initially, the cells proliferated but lost their naïve characteristics and died with prolonged exposure. Continuous IL-7 treatment also led the cells to produce high levels of interferon-gamma (IFN-g). In contrast, when the researchers treated the cells with intermittent IL-7 by applying the cytokine for 14 hours then washing the cells and culturing them without IL-7 for 10 hours for several days, the cells neither grew nor died and retained their naïve phenotype. Thus, even in the absence of TCR signaling, intermittent IL-7 treatment was able to maintain a quiescent pool of naïve T cells.

This was the first demonstration that continuous exposure to IL-7 could cause T cells to die, and the scientists wanted to determine the mechanism of this cytokine-induced cell death (CICD). They found that prolonged IL-7 exposure stimulated the expression of pro-apoptotic proteins including active caspase-3, Fas, Fas ligand, and Bim. Since continuous IL-7 induced both IFN-g and CICD, the researchers asked whether IFN-g played a role in IL-7-mediated CICD. Exposing 7RTg T cells lacking the IFN-g gene to recombinant IFN-g enhanced the cell death caused by IL-7 treatment. Reciprocally, treating the 7RTg T cells with an anti-IFN-g antibody prevented IL-7-mediated apoptosis and even led to exponential cell growth. In fact, 7RTg T cells were able to proliferate and to survive in mice deficient in TCR self-ligands when the researchers treated them every other day with the anti-IFN-g antibody, revealing the essential role of IFN-g in CICD due to IL-7 in vivo.

In light of their data, the investigators hypothesized that endogenous TCR activation should limit continuous IL-7 signaling and thus CICD. In support of their hypothesis, TCR binding to self-ligands inhibited the expression of IFN-g and Fas ligand in both 7RTg and normal T cells. Indeed, the stronger the TCR signal the more the IL-7 signal was interrupted and the more of these cells that survived.

Taken together, the researchers’ findings show that the complex interplay between IL-7 and TCR signaling pathways allows only those cells with sufficient TCR activity to thwart IL-7-mediated CICD to survive in vivo and maintains the population of naïve T cells necessary for immunocompetence.

Kimura MY, Pobezinsky LA, Guinter TI, Thomas J, Adams A, Park JH, Tai X, and Singer A. IL-7 signaling must be intermittent, not continuous, during CD8(+) T cell homeostasis to promote cell survival instead of cell death. Nat Immunol. December 16, 2012. Pubmed Link