Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy.

Background: Allergen-specific immunotherapy is a disease-modifying treatment that induces long-term T-cell tolerance.

Objective: We sought to evaluate the role of circulating CXCR5PD-1 T follicular helper (cT) and T follicular regulatory (T) cells following grass pollen subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) and the accompanying changes in their chromatin landscape.

Methods: Phenotype and function of cT cells were initially evaluated in the grass pollen-allergic (GPA) group (n = 28) and nonatopic healthy controls (NAC, n = 13) by mathematical algorithms developed to manage high-dimensional data and cell culture, respectively. cT and T cells were further enumerated in NAC (n = 12), GPA (n = 14), SCIT- (n = 10), and SLIT- (n = 8) treated groups. Chromatin accessibility in cT and T cells was assessed by assay for transposase-accessible chromatin sequencing (ATAC-seq) to investigate epigenetic mechanisms underlying the differences between NAC, GPA, SCIT, and SLIT groups.

Results: cT cells were shown to be distinct from T2- and T2A-cell subsets, capable of secreting IL-4 and IL-21. Both cytokines synergistically promoted B-cell class switching to IgE and plasma cell differentiation. Grass pollen allergen induced cT-cell proliferation in the GPA group but not in the NAC group (P < .05). cT cells were higher in the GPA group compared with the NAC group and were lower in the SCIT and SLIT groups (P < .01). Time-dependent induction of IL-4, IL-21, and IL-6 was observed in nasal mucosa following intranasal allergen challenge in the GPA group but not in SCIT and SLIT groups. T and IL-10 cT cells were induced in SCIT and SLIT groups (all, P < .01). ATAC-seq analyses revealed differentially accessible chromatin regions in all groups.

Conclusions: For the first time, we showed dysregulation of cT cells in the GPA group compared to NAC, SCIT, and SLIT groups and induction of T and IL-10 cT cells following SCIT and SLIT. Changes in the chromatin landscape were observed following allergen-specific immunotherapy in cT and T cells.