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

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-2stimulated 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.