Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10-dependent Treg–microglia crosstalk
Neuroinflammation plays a crucial role in traumatic brain injury (TBI), contributing to both damage and recovery, yet no effective therapy exists to mitigate central nervous system (CNS) injury and promote recovery after TBI. In the present study, we found that nasal administration of an anti-CD3 monoclonal antibody ameliorated CNS damage and behavioral deficits in a mouse model of contusional TBI. Nasal anti-CD3 induced a population of interleukin (IL)-10-producing regulatory T cells (T<sub>reg</sub> cells) that migrated to the brain and closely contacted microglia. T<sub>reg</sub> cells directly reduced chronic microglia inflammation and regulated their phagocytic function in an IL-10-dependent manner. Blocking the IL-10 receptor globally or specifically on microglia in vivo abrogated the beneficial effects of nasal anti-CD3. However, the adoptive transfer of IL-10-producing T<sub>reg</sub> cells to TBI-injured mice restored these beneficial effects by enhancing microglial phagocytic capacity and reducing microglia-induced neuroinflammation. These findings suggest that nasal anti-CD3 represents a promising new therapeutic approach for treating TBI and potentially other forms of acute brain injury.
Authors
- Toby B. Lanser (ORCID: https://orcid.org/0000-0002-2250-6075)
- Francisco J. Quintana (ORCID: https://orcid.org/0000-0001-8156-0736)
- Joshua D. Bernstock (ORCID: https://orcid.org/0000-0002-7814-3867)
- Patrick da Silva (ORCID: https://orcid.org/0000-0002-3481-4972)
- Oleg Butovsky (ORCID: https://orcid.org/0000-0003-0186-8867)
- Rafael M. Rezende (ORCID: https://orcid.org/0000-0003-3998-8012)
- Federico Montini (ORCID: https://orcid.org/0000-0002-8367-0741)
- Tian Cao
- Kusha Chopra (ORCID: https://orcid.org/0009-0006-6248-7450)
- Marília Gerhardt de Oliveira (ORCID: https://orcid.org/0000-0002-1450-2306)
- Masen L. Boucher
- Wesley Nogueira Brandão (ORCID: https://orcid.org/0000-0001-9306-3251)
- Rebekah Mannix (ORCID: https://orcid.org/0000-0003-3608-2792)
- Joon-Hyuk Lee (ORCID: https://orcid.org/0000-0002-6249-4291)
- Omar Albastaki
- Danielle S. LeServe (ORCID: https://orcid.org/0009-0006-7020-9928)
- Hadi Abou‐El‐Hassan (ORCID: https://orcid.org/0000-0002-2765-291X)
- Saef Izzy (ORCID: https://orcid.org/0000-0002-2822-6736)
- Howard L. Weiner (ORCID: https://orcid.org/0000-0003-0203-9681)
- Leah C. Beauchamp (ORCID: https://orcid.org/0000-0002-4896-279X)
- Taha Yahya (ORCID: https://orcid.org/0009-0009-6636-0117)
- Rajesh Krishnan (ORCID: https://orcid.org/0000-0002-9171-3422)
- Gabriel Pasquarelli-do-Nascimento (ORCID: https://orcid.org/0000-0002-8329-343X)
- Thaís G. Moreira (ORCID: https://orcid.org/0000-0002-0007-9498)
- Michael Aronchik
- K. Lu
- Ana Durao
- Megha Kaul
Institutions
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Harvard University (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-02-27
- DOI
- https://doi.org/10.1038/s41593-025-01877-7
- Citations
- 30
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 25.27