Research ArticleImmunology

IL-2Rβ abundance differentially tunes IL-2 signaling dynamics in CD4+ and CD8+ T cells

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Science Signaling  19 Dec 2017:
Vol. 10, Issue 510, eaan4931
DOI: 10.1126/scisignal.aan4931

Receptor abundance defines signaling dynamics

Although the cytokine interleukin-2 (IL-2) stimulates the same receptors and intracellular signaling components in CD4+ and CD8+ T cells, these cells exhibit different responses to IL-2. Both cell types proliferate in response to IL-2, but CD8+ T cells enter the S phase earlier and are more proliferative than CD4+ T cells. Smith et al. found that whereas IL-2 stimulated sustained phosphorylation of the transcription factor STAT5 in CD8+ T cells, it caused CD4+ T cells to exhibit two phases of STAT5 phosphorylation. The IL-2 receptor subunit IL-2Rβ was less abundant in CD4+ T cells than in CD8+ T cells. Reducing IL-2Rβ in CD8+ T cells made these cells exhibit a CD4+ T cell–like pattern of STAT5 phosphorylation and delayed cell cycle entry. These distinct IL-2 signaling dynamics may tune the responses of CD4+ and CD8+ T cells to enable an adequate immune response while protecting against autoimmunity.


Interleukin-2 (IL-2) stimulates both activated CD4+ and CD8+ T cells to proliferate. IL-2 signals through an identical receptor complex and promotes the same dose-dependent phosphorylation of the canonical transcription factor STAT5 in both cell types. Despite this, CD8+ T cells enter the S phase earlier and proliferate to a greater extent than do CD4+ T cells in response to IL-2. We identified distinct IL-2 signaling dynamics in CD4+ and CD8+ T cells. In IL-2–stimulated CD8+ T cells, STAT5 phosphorylation increased rapidly and was sustained for 6 hours. In contrast, CD4+ T cells had a biphasic response, with maxima at 15 min and 2 to 4 hours after stimulation. Both cell types required vesicular trafficking, but only CD4+ T cells required new protein synthesis to maintain high phosphorylation of STAT5. Two subunits of the IL-2 receptor, IL-2Rβ and IL-2Rγ, were twice as abundant in CD8+ T cells than in CD4+ T cells. Reduction of IL-2Rβ abundance by 50% was sufficient to convert CD8+ T cells to a CD4+ T cell–like signaling pattern and delay S phase entry. These results suggest that the larger pool of IL-2Rβ chains in CD8+ T cells is required to sustain IL-2 signaling and contributes to the quantitatively greater proliferative response to IL-2 relative to that of CD4+ T cells. This cell type–specific difference in IL-2Rβ abundance appears to tune responses, potentially preventing extensive, autoimmune proliferation of CD4+ T cells, while still enabling sufficient proliferation of CD8+ T cells to control viral infections.

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