Distinct Disease-specific Tfh Cell Populations in 2 Different Fibrotic Diseases: IgG-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 (IgG-related disease, IgG-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-RD.

Results: Infiltrating Tfh cells in tertiary lymphoid organs from IgG-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10-expressing LAG3 Tfh cells in patients with IgG-RD. Furthermore, we found that infiltrating AICDACD19 B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG 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-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG-RD; in contrast, type 2 immune cells were abundant in KD.

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