Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition
The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.
Authors
- Ricardo A. Fernandes (ORCID: https://orcid.org/0000-0001-5343-3334)
- Juliana Sucharov (ORCID: https://orcid.org/0000-0002-0979-3903)
- Gita C. Abhiraman (ORCID: https://orcid.org/0000-0002-0546-4133)
- Saul Villeda (ORCID: https://orcid.org/0000-0002-2726-9582)
- Matthew T. Buckley
- Andy P. Tsai (ORCID: https://orcid.org/0000-0001-6400-544X)
- Max Hauptschein (ORCID: https://orcid.org/0000-0002-8478-568X)
- Giulia Notarangelo (ORCID: https://orcid.org/0000-0003-3805-1834)
- Paloma Navarro Negredo (ORCID: https://orcid.org/0000-0003-1087-3895)
- Julliana Ramirez-Matias (ORCID: https://orcid.org/0000-0003-2228-1440)
- Justin You (ORCID: https://orcid.org/0009-0009-0002-4540)
- Adam B. Schroer (ORCID: https://orcid.org/0000-0002-4038-733X)
- Karen Malacon (ORCID: https://orcid.org/0000-0002-4782-0466)
- Daniel Richard (ORCID: https://orcid.org/0000-0001-8568-9473)
- Lucy Xu (ORCID: https://orcid.org/0000-0001-6765-463X)
- Olivia Y. Zhou (ORCID: https://orcid.org/0000-0003-2107-2567)
- Anne Brunet (ORCID: https://orcid.org/0000-0002-4608-6845)
- Eric Sun (ORCID: https://orcid.org/0000-0001-8805-9864)
- Eduardo Ramirez Lopez
- Tony Wyss-Coray
- Robert A. Saxton
- K. Christopher Garcia
Institutions
- University of California, San Francisco (US)
- Neurosciences Institute (US)
- University of San Francisco (US)
- Stanford University (US)
Publication Details
- Journal
- Immunity
- Published
- 2026-01-30
- DOI
- https://doi.org/10.1016/j.immuni.2026.01.016
- Citations
- 1
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 30.63