IL-2 can signal via chemokine receptors to promote regulatory T cells’ suppressive function
Hao Sun, Ho Sup Lee, S H Kim, Mikhael Fernandes de Lima, Alexandre R. Gingras, Qinyi Du, Wilma McLaughlin, Jailail Ablack, Miguel Alejandro Lopez‐Ramirez, Frédéric Lagarrigue, Zhichao Fan, John T. Chang, Derek VanDyke, Jamie B. Spangler, Mark H. Ginsberg
Abstract
Canonical interleukin-2 (IL-2) signaling via the high-affinity CD25-containing IL-2 receptor-Janus kinase (JAK)1,3-signal transducer and activator of transcription 5 (STAT5) pathway is essential for development and maintenance of CD4 + CD25 Hi Foxp3 + regulatory T cells (Tregs) that support immune homeostasis. Here, we report that IL-2 signaling via an alternative CD25-chemokine receptor pathway promotes the suppressive function of Tregs. Using an antibody against CD25 that biases IL-2 signaling toward this alternative pathway, we establish that this pathway increases the suppressive activity of Tregs and ameliorates murine experimental autoimmune encephalomyelitis (EAE). Furthermore, heparan sulfate, an IL-2-binding element of cell surfaces and extracellular matrix, or an engineered IL-2 immunocytokine can also direct IL-2 signaling toward this alternative pathway. Overall, these data reveal a non-canonical mechanism for IL-2 signaling that promotes suppressive functions of Tregs, further elucidates how IL-2 supports immune homeostasis, and suggests approaches to promote or suppress Treg functions.