How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell–dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG₄ (IgG₄-related disease, IgG₄-RD) can provide important insights regarding cytokine expression by Tfh cells.

We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes).

Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG₄-RD.

Infiltrating Tfh cells in tertiary lymphoid organs from IgG₄-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10–expressing LAG3⁺ Tfh cells in patients with IgG₄-RD. Furthermore, we found that infiltrating AICDA⁺CD19⁺ B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG₄ expression. In contrast, we found that infiltrating IL-13–expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13–expressing Tfh cells in tissues from patients with IgG₄-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG₄-RD; in contrast, type 2 immune cells were abundant in KD.

Our analysis revealed a novel subset of IL-10⁺LAG3⁺ Tfh cells infiltrating the affected organs of IgG₄-RD patients. In contrast, IL-13⁺ Tfh cells and type 2 immune cells infiltrated those of KD patients.