IL-27 promotes Treg cell expression of CD122 and fitness at homeostasis
Regulatory T (Treg) cells express high levels of the IL-27R, and in the setting of infection and autoimmunity, the cytokine IL-27 promotes Treg cell activities that mitigate tissue pathology. However, IL-27 appears dispensable for Treg cell development and maintenance as lineage-specific depletion of the IL-27R on Treg cells does not impact these populations at steady state. In contrast, when mice were generated in which the Treg compartment comprised a mix of IL-27R-sufficient and -deficient Treg cells, those that lacked IL-27R were at a competitive disadvantage. Aging experiments illustrate that IL-27R-deficient Treg cells are preferentially eroded, and this defect was associated with reduced expression of CD122, the β chain of the IL-2/15R. Moreover, blockade of CD122 led to a similar loss of Treg cells, and in vitro and in vivo studies highlight that IL-27 promotes Treg cell expression of CD122 and improves responsiveness to IL-2/15. These datasets reveal that homeostatic IL-27 signals provide a competitive advantage that shapes the composition of the Treg cell pool by modulating responsiveness to growth factors.
Authors
- Christopher A. Hunter (ORCID: https://orcid.org/0000-0003-3092-1428)
- Elisa Cruz-Morales (ORCID: https://orcid.org/0000-0003-4902-4372)
- Booki Min (ORCID: https://orcid.org/0000-0002-2151-9413)
- Christian A. Howard
- Joseph A. Pereira (ORCID: https://orcid.org/0000-0003-2341-8461)
- Melissa Parker (ORCID: https://orcid.org/0009-0008-8895-6643)
- Zachary Lanzar
- Zhe Zhong (ORCID: https://orcid.org/0009-0004-1125-4441)
- Chryssa Kanellopoulou
- Aaron M. Ring (ORCID: https://orcid.org/0000-0003-3699-2446)
- David A. Christian (ORCID: https://orcid.org/0000-0002-7160-9900)
- Ross M. Kedl (ORCID: https://orcid.org/0000-0002-9065-7895)
- Daniel L. Aldridge (ORCID: https://orcid.org/0000-0003-2224-5159)
- Anthony T. Phan (ORCID: https://orcid.org/0000-0003-2935-6070)
- Julia Eberhard (ORCID: https://orcid.org/0009-0008-5134-9671)
- Isabella O. Conway (ORCID: https://orcid.org/0009-0009-5987-1373)
Institutions
- Northwestern University (US)
- Harvard University (US)
- Fred Hutch Cancer Center (US)
- Boston VA Research Institute (US)
- University of Colorado Anschutz Medical Campus (US)
- University of Pennsylvania (US)
- Incyte (United States) (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1073/pnas.2519141122
- Citations
- 1
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.80