The Common Cytokine Receptor γ Chain Plays an Essential Role in Regulating Lymphoid Homeostasis

In the immune system, there is a careful regulation not only of lymphoid development and proliferation, but also of the fate of activated and proliferating cells. Although the manner in which these diverse events are coordinated is incompletely understood, cytokines are known to play major roles. Whereas IL-7 is essential for lymphoid development, IL-2 and IL-4 are vital for lymphocyte proliferation. The receptors for each of these cytokines contain the common cytokine receptor γ chain (γ_c), and it was previously shown that γ_c-deficient mice exhibit severely compromised development and responsiveness to IL-2, IL-4, and IL-7. Nevertheless, these mice exhibit an age-dependent accumulation of splenic CD4⁺ T cells, the majority of which have a phenotype typical of memory/activated cells. When γ_c-deficient mice were mated to DO11.10 T cell receptor (TCR) transgenic mice, only the T cells bearing endogenous TCRs had this phenotype, suggesting that its acquisition was TCR dependent. Not only do the CD4⁺ T cells from γ_c-deficient mice exhibit an activated phenotype and greatly enhanced incorporation of bromodeoxyuridine but, consistent with the lack of γ_c-dependent survival signals, they also exhibit an augmented rate of apoptosis. However, because the CD4⁺ T cells accumulate, it is clear that the rate of proliferation exceeds the rate of cell death. Thus, surprisingly, although γ_c-independent signals are sufficient to mediate expansion of CD4⁺ T cells in these mice, γ_c-dependent signals are required to regulate the fate of activated CD4⁺ T cells, underscoring the importance of γ_c-dependent signals in controlling lymphoid homeostasis.