Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides

Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2R) are an indicator of poor prognosis in patients with B-cell non-Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2R upregulates Foxp3 expression and induces the development of regulatory T (T-reg) cells. Methods To inhibit the binding of IL-2 to sIL-2R with the goal of suppressing the induction of Foxp3 and decreasing T-reg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2R. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL-2R binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL-2R signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-]) and granules (perforin/granzyme B) was preserved in CD8(+) T cells co-cultured with IL-2-stimulated CD4(+) T cells that had been pretreated with CMD178 compared to CD8(+) cells co-cultured with untreated IL-2-stimulated CD4(+) T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL-2R signaling and inhibit T-reg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies.