Negative Feedback Regulation of T Cells via Interleukin-2 and FOXP3 Reciprocity

As interleukin-2 (IL2) is central to the clonal expansion of antigen-selected T cells, we investigated the relationship between IL2 and the negative regulatory transcription factor FOXP3. We found IL2 to be responsible for T cell antigen receptor (TCR)-activated FOXP3 expression by both CD4+ and CD8+ human T cells, and as anticipated, FOXP3 expression restricted TCR-stimulated IL2 expression. However, no evidence could be found that FOXP3+ cells actively suppress IL2 expression by FOXP3- cells. These data are consistent with an IL2/FOXP3-dependent negative feedback loop that normally regulates the T cell immune response. It follows that a defect in this negative feedback loop as a result of a deficiency of either IL2 or FOXP3 will lead to a hyperproliferative autoimmune syndrome, without the necessity of invoking an active suppressive function for FOXP3+ T cells

Crystal structure of the IL-2 signaling complex: Paradigm for a heterotrimeric cytokine receptor

IL-2 is a cytokine that functions as a growth factor and central regulator in the immune system and mediates its effects through ligand-induced hetero-trimerization of the receptor subunits IL-2Rα, IL-2Rβ, and γ(c). Here, we describe the crystal structure of the trimeric assembly of the human IL-2 receptor ectodomains in complex with IL-2 at 3.0 Å resolution. The quaternary structure is consistent with a stepwise assembly from IL-2/IL-2Rα to IL-2/IL-2Rα/IL-2Rβ to IL-2/IL-2Rα/IL-2Rβ/γ(c). The IL-2Rα subunit forms the largest of the three IL-2/IL-2R interfaces, which, together with the high abundance of charge–charge interactions, correlates well with the rapid association rate and high-affinity interaction of IL-2Rα with IL-2 at the cell surface. Surprisingly, IL-2Rα makes no contacts with IL-2Rβ or γ(c), and only minor changes are observed in the IL-2 structure in response to receptor binding. These findings support the principal role of IL-2Rα to deliver IL-2 to the signaling complex and act as regulator of signal transduction. Cooperativity in assembly of the final quaternary complex is easily explained by the extraordinarily extensive set of interfaces found within the fully assembled IL-2 signaling complex, which nearly span the entire length of the IL-2Rβ and γ(c) subunits. Helix A of IL-2 wedges tightly between IL-2Rβ and γ(c) to form a three-way junction that coalesces into a composite binding site for the final γ(c) recruitment. The IL-2/γ(c) interface itself exhibits the smallest buried surface and the fewest hydrogen bonds in the complex, which is consistent with its promiscuous use in other cytokine receptor complexes