IL-2 can signal via chemokine receptors to promote regulatory T cells’ suppressive function

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112996
• Main Authors: Sun, Hao, Lee, Ho-Sup, Kim, Sarah Hyun-Ji, Fernandes de Lima, Mikhael, 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., Ginsberg, Mark H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 29.08.2023; Elsevier
• Subjects: Animals; autoimmunity; CD25; chemokine receptor; CP: Immunology; Encephalomyelitis, Autoimmune, Experimental; experimental autoimmune encephalomyelitis; Forkhead Transcription Factors - metabolism; heparan sulfate; IL-2; IL-2 receptor; integrins; Interleukin-2 - metabolism; Interleukin-2 Receptor alpha Subunit - metabolism; Life Sciences; Mice; Receptors, Chemokine - metabolism; Receptors, Interleukin-2 - metabolism; regulatory T cells; Signal Transduction; T-Lymphocytes, Regulatory; CP: Immunology; integrins; experimental autoimmune encephalomyelitis; heparan sulfate; regulatory T cells; autoimmunity; signal transduction; IL-2 receptor; IL-2; CD25; chemokine receptor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112996

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. [Display omitted] •IL-2 can signal via chemokine receptors (CRs) in addition to the βγ IL-2 receptors•An anti-CD25 induces a CD25-IL-2-CCR7 complex and enforces CR signaling•This non-canonical IL-2 signaling pathway promotes Tregs’ suppressive function•A modified form of this anti-CD25 ameliorates experimental autoimmunity IL-2 shapes the immune response. Sun et al. report that IL-2 signaling via a CD25-chemokine receptor pathway promotes increased regulatory T cells’ suppressive function. An anti-CD25 or heparan sulfate biases IL-2 signaling toward this chemokine receptor pathway, and administration of a modified form of this anti-CD25 ameliorates murine experimental autoimmune encephalomyelitis.