IL-2 Receptor - T Cell Proliferation

T Cell Proliferation

Once IL-2 binds to the external domains of the IL-2R and the cytoplasmic domains are engaged, signaling continues until the IL-2/IL-2R complex is internalized and degraded. However, each cell only decides to make the irrevocable commitment to replicate its DNA and undergo mitosis and cytokinesis when a critical number of IL-2Rs have been triggered. Given that the half-time for internalization of IL-2 occupied IL-2Rs is ~ 15 minutes, it is possible to calculate the number of triggered IL-2Rs necessary. Thus, the critical number of triggered IL-2Rs is ~ 30,000. In as much that the mean number of high affinity IL-2Rs on antigen-activated T cells is only ~ 1,000, it appears that new receptors must be synthesized before the cell makes the quantal, all-or-none decision to divide. Accordingly, a mean of at least 11 hours of IL-2/IL-2R interaction are necessary before a cell decides to undergo DNA replication.

Until recently, the intracellular molecules activated by the IL-2R at the cell membrane that are responsible for promoting cell cycle progression were obscure. However, early on it was shown that IL-2Rs triggered the expression of cyclin D2 and cyclin D3. Now it is known that the STAT5a/b molecules activated by the IL-2R via the JAK1/3 kinases promote the transcriptional activation of the D cyclins. As well, via the activation of the PI3K pathway, an inhibitor of cyclin-D/CDK activity (p27) is targeted for degradation. Both of these biochemical events, as well as others activated via the IL-2R ultimately promote progression through G1 of the cell cycle and through the G1 restriction point, thereby triggering the onset of DNA synthesis and replication.

The IL-2R also signals negative feedback loops that function to inhibit IL-2 gene expression. These loops either shut down signaling via the T cell antigen receptor by activating the expression of CTLA-4, or by activating the expression of FOXP3, which as a negative regulator of IL-2 transcription operates at the level of the IL-2 promoter.

Other recent data indicate that T cells that express FOXP3 (T regulatory cells) can suppress other T cells by binding IL-2 via the high affinity IL-2R, and followed by internalization of the quaternary IL-2/IL-2R complex, degrade IL-2. Thus, the concentration of IL-2 available determines the tempo, magnitude and extent of T cell immune responses.