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

Abstract

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-2R and IL-2R, were twice as abundant in CD8+ T cells than in CD4+ T cells. Reduction of IL-2R 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-2R 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-2R 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.