Non-canonical IL-2 signaling facilitates peripheral regulatory T cell differentiation

Non-canonical IL-2 signaling, termed M onoclonal antibody or M atrix-directed A lternative C ytokine S ignaling (MACS), is mediated by a CD25-chemokine receptor complex and operates in concert with the canonical JAK-STAT5 pathway; however, its role in T cell homeostasis remains poorly defined. Here, we uncover a role for MACS in regulatory T cell (Treg) differentiation and functional specification. We generated Il2 ^{E66K /E66K} mice in which CD25-CCR7 assembly is disrupted and IL-2-induced STAT5 phosphorylation is preserved. Immunophenotyping analysis by flow cytometry revealed that MACS deficiency reduces the accumulation of Nrp1 ^- Foxp3 ⁺ Tregs in gut-associated lymphoid tissues from 24-weeks-old Il2 ^E66K/E66K mutant mice. Single-cell transcriptomics, functional suppression assays, and in vitro differentiation revealed that MACS engagement drives Treg differentiation and sustains effector Treg programs-marked by robust IL-10 expression-in part via an AP-1-dependent transcriptional network. These findings establish IL-2 MACS as a distinct signal directing peripheral immune tolerance and highlight a potential node for targeted immunomodulation.

Non-canonical IL-2 signaling facilitates gut regulatory T cell development and suppressive function.