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.