Work

A CD25–chemokine receptor complex initiates noncanonical IL-2 signaling

Year: 2025

Type: article

Abstract: An anti-mouse CD25 antibody, PC61, induces a complex formed by the IL-2-dependent association of CD25 with CCR7 and an alternative IL-2 signaling pathway that results in integrin activation in CD4 + CD25 Hi Foxp3 + regulatory T cells (Treg). Here, we used structure-based design together with combinatorial screening to identify a human IL-2 mutant (IL-2(E52K)) that disrupts CD25-CCR7 complex formation while retaining the full CD25 affinity of the parent molecule. An anti-human CD25, 7G7B6, drove formation of IL-2–dependent human CD25-CCR7, CD25-CXCR4, and CD25-CCR5 complexes and induced integrin activation in human CD25-expressing IL-2Rα + YT-1 cells, Jurkat T cells and primary Tregs. IL-2(E52K) failed to support activation in CCR5 Lo Jurkat T cells and primary Tregs. In contrast, IL-2(E52K) supported activation in CCR5 Hi IL-2Rα + YT-1 cells which was blocked by the CCR5-specific antagonist, Maraviroc. Heparan sulfate (HS), a physiological ligand of IL-2, induced IL-2-dependent CD25-CCR7 association and IL-2(E52K) failed to support HS-induced CD25-CCR7 complex formation and integrin activation in Jurkat cells. Both HS and 7G7B6 did not block canonical IL-2 signaling. CD122 was present in the 7G7B6-induced CCR7-CD25 complex. CD122 forms a heterodimer with CD132 (the common γ chain) that triggers canonical IL-2 signaling. Thus, both anti-CD25 antibody and HS require formation of a chemokine receptor-CD25 complex to initiate alternative IL-2 signaling. In addition, our findings suggest that alternative and canonical IL-2 signaling receptors can be incorporated into the same multi-protein assembly, allowing for a single complex to mediate divergent effects on downstream signaling.

Source: Journal of Biological Chemistry

DOI: 10.1016/j.jbc.2025.110981