1. IL-2 can signal via chemokine receptors to promote regulatory T cells’ suppressive function
- Author
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Sun, Hao, Lee, Ho-Sup, Kim, Sarah Hyun-Ji, de Lima, Mikhael Fernandes, Gingras, Alexandre R, Du, Qinyi, McLaughlin, Wilma, Ablack, Jailail, Lopez-Ramirez, Miguel A, Lagarrigue, Frederic, Fan, Zhichao, Chang, John T, VanDyke, Derek, Spangler, Jamie B, and Ginsberg, Mark H
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Neurodegenerative ,Neurosciences ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Mice ,Animals ,T-Lymphocytes ,Regulatory ,Interleukin-2 ,Receptors ,Chemokine ,Interleukin-2 Receptor alpha Subunit ,Receptors ,Interleukin-2 ,Signal Transduction ,Encephalomyelitis ,Autoimmune ,Experimental ,Forkhead Transcription Factors ,CD25 ,CP: Immunology ,IL-2 ,IL-2 receptor ,autoimmunity ,chemokine receptor ,experimental autoimmune encephalomyelitis ,heparan sulfate ,integrins ,regulatory T cells ,signal transduction ,Medical Physiology ,Biological sciences - 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+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.
- Published
- 2023