Antibody durability is influenced by interleukin-2 production by undifferentiated memory T helper cells and extensive B cell clonal expansion

• Published in: Cell reports (Cambridge) Vol. 44; no. 7; p. 115934
• Main Authors: Isogawa, Masanori, Shinoda, Masahiro, Kotaki, Ryutaro, Terahara, Kazutaka, Onodera, Taishi, Kabasawa, Kiyomi, Toyama-Kousaka, Mio, Fujisawa, Mizuki, Watanabe, Mitsukaze, Tonouchi, Keisuke, Terooatea, Tommy, Kitano, Ayumi, Adachi, Yu, Moriyama, Saya, Takano, Tomohiro, Fukushi, Shuetsu, Matsumura, Takayuki, Yamashita, Kazuo, Shinkai, Masaharu, Takahashi, Yoshimasa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.07.2025; Elsevier
• Subjects: Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; antibody durability; B-Lymphocytes - immunology; BACH2; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; COVID-19 - immunology; COVID-19 - prevention & control; CP: Immunology; helper T cells; Humans; Immunologic Memory; interleukin-2; Interleukin-2 - biosynthesis; Interleukin-2 - immunology; Interleukin-2 - metabolism; Interleukin-21; Memory T Cells - immunology; mRNA vaccine; SARS-CoV-2 - immunology; Spike Glycoprotein, Coronavirus - immunology; T-Lymphocytes, Helper-Inducer - immunology; CP: Immunology; interleukin-2; antibody durability; helper T cells; BACH2; mRNA vaccine
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115934

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+ T cells to produce interleukin (IL)-2 and T helper type 2 (Th2) cytokines. IL-2 production by CD4+ 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+ 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. [Display omitted] •Post-booster neutralizing antibodies wane slowly in the sustainer group•IL-2-producing potential in memory T cells differs in the sustainer group•IL-2-producing potential predicts sustained antibody titers at post-booster•IL-2+ T cells are memory Th0 cells expressing BACH2 and helper molecules Isogawa et al. show that antibody durability after booster vaccination is predicted by pre-existing memory T cells that produce IL-2 upon antigen stimulation. These memory T cells, termed memory Th0 cells, uniquely express BACH2, distinguishing them from conventional helper T cells.