Th2-skewed peripheral T helper cells drives B cells in allergic bronchopulmonary aspergillosis

Abstract

Introduction: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. However, the involvement of T cell subsets remains unclear.

Methods: We enrolled ABPA patients, asthma patients and healthy controls. Th1, Th2, Th17, Treg and IL-21⁺CD4⁺T cells in total or sorted subsets of peripheral blood mononuclear cells (PBMCs) and ABPA Bronchoalveolar Lavage fluid (BALF) were analyzed by flow cytometry. RNA sequencing of subsets of CD4⁺T cells were done in exacerbated ABPA patients and healthy controls. Antibodies of T-B cell co-cultures in vitro were measured.

Results: ABPA patients had increased Th2 cells, similar Treg cells and decreased circulating Th1 and Th17 cells. IL-5⁺IL-13⁺IL-21⁺CD4⁺T cells was rarely detected in healthy controls but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5⁺IL-13⁺IL-21⁺CD4⁺T cells were mainly peripheral T helper (Tph) cells (PD-1⁺CXCR5^-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph were similar among ABPA patients, asthma patients and healthy controls, while IL-5⁺IL-13⁺IL-21⁺ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T helper (Tfh) cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B cells into plasmablasts and significantly enhanced the production of IgE.

Conclusion: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.