Distinct disease-specific Tfh cell populations in 2 different fibrotic diseases: IgG(4)-related disease and Kimura disease.

BACKGROUND: 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 IgG(4) (IgG(4)-related disease, IgG(4)-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: 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). METHODS: 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 IgG(4)-RD. RESULTS: Infiltrating Tfh cells in tertiary lymphoid organs from IgG(4)-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10-expressing LAG3(+) Tfh cells in patients with IgG(4)-RD. Furthermore, we found that infiltrating AICDA(+)CD19(+) B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG(4) 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 IgG(4)-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG(4)-RD; in contrast, type 2 immune cells were abundant in KD. CONCLUSIONS: Our analysis revealed a novel subset of IL-10(+)LAG3(+) Tfh cells infiltrating the affected organs of IgG(4)-RD patients. In contrast, IL-13(+) Tfh cells and type 2 immune cells infiltrated those of KD patients.