Peanut allergy oral immunotherapy drives single-cell multi-omic changes in peanut-reactive T cells associated with sustained unresponsiveness
Oral immunotherapy (OIT) is the only U.S. Food and Drud Administration-approved treatment for peanut allergy. Peanut-reactive (pr) CD4<sup>+</sup> T cells are pivotal in peanut allergy pathogenesis and OIT-induced desensitization. However, the underlying pr CD4<sup>+</sup> T cell immune mechanisms leading to sustained unresponsiveness after OIT discontinuation are largely unknown. We analyzed single-cell RNA and protein immunophenotypes and T cell receptor repertoires of pr CD4<sup>+</sup> T cells from a phase 2 peanut OIT trial cohort. We identified increased cytotoxicity-related phenotypes and type 1 helper cytotoxic T lymphocyte-like cell clonal expansion during OIT, while type 2 helper T (T<sub>H</sub>2) cell-related phenotypes and T<sub>H</sub>2-like cell clonal expansion decreased. OIT participants achieving sustained unresponsiveness were distinguished by lower baseline T<sub>H</sub>2-related phenotypes, elevated post-OIT cytotoxicity-related pr effector T cell gene signatures and higher CD39 expression in pr regulatory T cells. These findings clarify OIT-induced CD4<sup>+</sup> T cell tolerance mechanisms and can guide effective allergen-specific OIT strategies.
Authors
- R. Sharon Chinthrajah (ORCID: https://orcid.org/0000-0003-2467-4256)
- Stephen J. Galli (ORCID: https://orcid.org/0000-0001-5736-5340)
- Jackson P. Schuetz (ORCID: https://orcid.org/0000-0002-1053-2903)
- Hana Seastedt
- Rosemarie H. DeKruyff (ORCID: https://orcid.org/0000-0002-3847-9446)
- Kari Christine Nadeau (ORCID: https://orcid.org/0000-0002-2146-2955)
- Ji-Yeun Lee (ORCID: https://orcid.org/0000-0002-0463-6802)
- Xuhuai Ji (ORCID: https://orcid.org/0000-0002-1768-6403)
- Maya Kasowski (ORCID: https://orcid.org/0000-0001-6583-0759)
- Ramona A. Hoh (ORCID: https://orcid.org/0000-0002-5116-1942)
- Scott D. Boyd (ORCID: https://orcid.org/0000-0003-0963-044X)
- Monali Manohar (ORCID: https://orcid.org/0000-0002-1869-2645)
- Holden T. Maecker (ORCID: https://orcid.org/0000-0003-0795-9946)
- Fabian Grubert
- Artem Mikelov (ORCID: https://orcid.org/0000-0002-1629-2373)
- Andrea Fernandes (ORCID: https://orcid.org/0000-0002-2855-4262)
- Shu Cao (ORCID: https://orcid.org/0000-0002-2992-8588)
- Arpita Singhal (ORCID: https://orcid.org/0000-0002-6515-6474)
- Xiaorui Han (ORCID: https://orcid.org/0000-0002-9058-3363)
- Valeria D Skatova
Institutions
- Harvard University (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-11-04
- DOI
- https://doi.org/10.1038/s41590-025-02323-3
- Citations
- 3
- Primary Topic
- Food Allergy and Anaphylaxis Research
- Type
- article
- Field-Weighted Citation Impact
- 4.87
Funders
- Johns Hopkins University
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases