IL-2 can signal via chemokine receptors to promote regulatory T cells’ suppressive function
Hao Sun,
Ho-Sup Lee,
Sarah Hyun-Ji Kim,
Mikhael Fernandes de Lima,
Alexandre R. Gingras,
Qinyi Du,
Wilma McLaughlin,
Jailail Ablack,
Miguel A. Lopez-Ramirez,
Frederic Lagarrigue,
Zhichao Fan,
John T. Chang,
Derek VanDyke,
Jamie B. Spangler,
Mark H. Ginsberg
Affiliations
Hao Sun
University of California San Diego School of Medicine, La Jolla, CA, USA
Ho-Sup Lee
University of California San Diego School of Medicine, La Jolla, CA, USA
Sarah Hyun-Ji Kim
University of California San Diego School of Medicine, La Jolla, CA, USA
Mikhael Fernandes de Lima
University of California San Diego School of Medicine, La Jolla, CA, USA
Alexandre R. Gingras
University of California San Diego School of Medicine, La Jolla, CA, USA
Qinyi Du
University of California San Diego School of Medicine, La Jolla, CA, USA
Wilma McLaughlin
University of California San Diego School of Medicine, La Jolla, CA, USA
Jailail Ablack
University of California San Diego School of Medicine, La Jolla, CA, USA
Miguel A. Lopez-Ramirez
University of California San Diego School of Medicine, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, La Jolla, CA, USA
Frederic Lagarrigue
Institute of Pharmacology and Structural Biology, Toulouse, France
Zhichao Fan
University of Connecticut School of Medicine, Farmington, CT, USA
John T. Chang
University of California San Diego School of Medicine, La Jolla, CA, USA
Derek VanDyke
Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
Jamie B. Spangler
Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
Mark H. Ginsberg
University of California San Diego School of Medicine, La Jolla, CA, USA; Corresponding author
Summary: 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+CD25HiFoxp3+ 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.
