Skip to content
DraconiticResearch
Search Sources API
203,203 studies31 sourcesUpdated 6 min ago
PreprintCC BYbioRxiv

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

  • A. Meecham
  • S. H. J. Kim
  • M. H. Fernandes de Lima
  • M. Tang
  • B. Liao
  • S. Chan
  • H.-s. Lee
  • L.-F. Lu
  • Z. Zhang
  • C. Jefferies
  • M. Guma
  • M.-A. Lopez-Ramirez
1 more authors
  • M. H. Ginsberg1
  1. 1Department of Medicine, University of California San Diego School of Medicine
Read full textPDFDOICite

Abstract

Non-canonical IL-2 signaling, termed Monoclonal antibody or Matrix-directed Alternative Cytokine Signaling (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 Il2E66K/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 Il2E66K/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.

Related

  1. Glutaminolysis and mTOR-C/EBPβ Signaling Drives the Differentiation of Novel IL-10-Producing Regulatory T Cells.
    Masaki Tajima, Ivan J Fuss, Naoko Ikuta +5
    International journal of molecular sciencesPeer-reviewedCC BYFull textImmunologyEurope PMC
  2. AtomWeaver: Multi-Component Flow Matching with a Structured Geometric Prior Facilitates Non-Canonical Peptide Design
    A. Kitaygorodsky, D. E. Hostallero, A. Broom +6
    bioRxivPreprintCC BYFull textSystems & synthetic biologybioRxiv
  3. WNK-SPAK/OSR1 signaling pathway facilitates ictal activity via reduced neuronal chloride extrusion rate
    V. I. Dzhala, F. H. Shiu, N. Rahmati +4
    bioRxivPreprintPublic domainFull textNeurosciencebioRxiv
  4. The PSR signaling pathway facilitates enrichment of P-solubilizing Burkholderia to enhance P acquisition in soybean
    Xiaoqian Wang, Jianfeng Lei, Kefei Zhang +10
    MicrobiomePeer-reviewedCC BY 4.0Plant biologyCrossref
  5. NLP6/7-mediated nitrate signaling facilitates high-affinity potassium uptake and enhances tolerance to low potassium environments in Arabidopsis.
    Kosuke Usuda, Mailun Yang, Namie Ohtsuki +4
    The Plant journal : for cell and molecular biologyPeer-reviewedCC BYFull textPlant biologyEurope PMC

Cite

BibTeXRIS
BibTeX
@misc{meecham2026noncanonical,
  title = {{Non-canonical IL-2 signaling facilitates peripheral regulatory T cell differentiation}},
  author = {A. Meecham and S. H. J. Kim and M. H. Fernandes de Lima and M. Tang and B. Liao and S. Chan and H.-s. Lee and L.-F. Lu and Z. Zhang and C. Jefferies and M. Guma and M.-A. Lopez-Ramirez and M. H. Ginsberg},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.07.756301},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.07.756301v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Non-canonical IL-2 signaling facilitates peripheral regulatory T cell differentiation
AU  - A. Meecham
AU  - S. H. J. Kim
AU  - M. H. Fernandes de Lima
AU  - M. Tang
AU  - B. Liao
AU  - S. Chan
AU  - H.-s. Lee
AU  - L.-F. Lu
AU  - Z. Zhang
AU  - C. Jefferies
AU  - M. Guma
AU  - M.-A. Lopez-Ramirez
AU  - M. H. Ginsberg
PY  - 2026
DA  - 2026/10/07
PB  - bioRxiv
DO  - 10.64898/2026.10.07.756301
UR  - https://www.biorxiv.org/content/10.64898/2026.10.07.756301v1
AB  - Non-canonical IL-2 signaling, termed Monoclonal antibody or Matrix-directed Alternative Cytokine Signaling (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 Il2E66K/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 Il2E66K/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.
ER  -