Antibody durability is influenced by interleukin-2 production by undifferentiated memory T helper cells and extensive B cell clonal expansion
SARS-CoV-2-neutralizing antibody titers serve as immune correlates of protection against COVID-19; however, the durability varies among vaccinees. Here, we demonstrate that the durability of vaccine-boosted antibody responses is closely correlated with the pre-booster capacity of spike-reactive CD4<sup>+</sup> T cells to produce interleukin (IL)-2 and T helper type 2 (Th2) cytokines. IL-2 production by CD4<sup>+</sup> T cells was also associated with extensive B cell clonal expansion, which preceded the durable antibody responses. High-dimensional cytometric and transcriptomic analyses revealed that IL-2-producing CD4<sup>+</sup> T cells exhibit low expression of markers characteristic of circulating T follicular helper cells or peripheral helper T cells. Nonetheless, IL-2-producing T cells highly express key helper molecules such as CD40L, ICOS, and IL-21, along with the transcription factor BACH2, which is known to prevent T cell differentiation and senescence. Thus, our study indicates a potential role of undifferentiated memory T helper cells in orchestrating the durability of antibody responses.
Authors
- Taishi Onodera (ORCID: https://orcid.org/0000-0002-7079-3339)
- Yoshimasa Takahashi (ORCID: https://orcid.org/0000-0001-6342-4087)
- Kazuo Yamashita (ORCID: https://orcid.org/0000-0002-7825-4719)
- Shuetsu Fukushi (ORCID: https://orcid.org/0000-0003-2718-6813)
- Tomohiro Takano (ORCID: https://orcid.org/0000-0003-4267-1147)
- Masaharu Shinkai (ORCID: https://orcid.org/0000-0002-4012-2518)
- Masahiro Shinoda (ORCID: https://orcid.org/0000-0002-0288-5637)
- Yu Adachi (ORCID: https://orcid.org/0000-0002-8573-987X)
- Masafumi Watanabe
- Takayuki Matsumura (ORCID: https://orcid.org/0000-0003-1760-3484)
- Ayumi Kitano
- Saya Moriyama (ORCID: https://orcid.org/0000-0003-2057-9198)
- Mizuki Fujisawa (ORCID: https://orcid.org/0000-0002-9491-0886)
- Masanori Isogawa (ORCID: https://orcid.org/0000-0001-8730-4303)
- Kazutaka Terahara (ORCID: https://orcid.org/0000-0001-9876-4356)
- Kiyomi Kabasawa
- Ryutaro Kotaki (ORCID: https://orcid.org/0000-0001-7965-1671)
- Keisuke Tonouchi
- Tommy Terooatea
- Mio Toyama‐Kousaka
Institutions
- National Institute of Infectious Diseases (JP)
- Seiwa Hospital (JP)
- New Tokyo Hospital (JP)
- TagCyx Biotechnologies (Japan) (JP)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-07-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115934
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Ministry of Health, Labour and Welfare