Altered chromatin landscape in circulating T follicular helper and regulatory cells following grass pollen subcutaneous and sublingual immunotherapy - 04/02/21
Abstract |
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 CXCR5+PD-1+ T follicular helper (cTFH) and T follicular regulatory (TFR) cells following grass pollen subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) and the accompanying changes in their chromatin landscape.
Methods |
Phenotype and function of cTFH 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. cTFH and TFR cells were further enumerated in NAC (n = 12), GPA (n = 14), SCIT- (n = 10), and SLIT- (n = 8) treated groups. Chromatin accessibility in cTFH and TFR 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 |
cTFH cells were shown to be distinct from TH2- and TH2A-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 cTFH-cell proliferation in the GPA group but not in the NAC group (P < .05). cTFH 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. TFR and IL-10+ cTFH 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 cTFH cells in the GPA group compared to NAC, SCIT, and SLIT groups and induction of TFR and IL-10+ cTFH cells following SCIT and SLIT. Changes in the chromatin landscape were observed following allergen-specific immunotherapy in cTFH and TFR cells.
Il testo completo di questo articolo è disponibile in PDF.Graphical abstract |
Key words : Allergy, seasonal allergic rhinitis, allergen-specific immunotherapy, T follicular helper cells, T follicular regulatory cells, chromatin accessibility, ATAC-seq
Abbreviations used : AIT, CSR, cTFH, CTLA-4, GC, GO, GPA, HDM, MAPK, NAC, SAR, SCIT, SLIT, SPADE, TFH, TFR, Treg
Mappa
| This research was funded by Royal Brompton Hospital charity research funds, United Kingdom and National Institute for Health Research (NIHR) Biomedical Research Centre, United Kingdom. |
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| Disclosure of potential conflict of interest: K. C. Nadeau reports grants from the National Institute of Allergy and Infectious Diseases (NIAID), Food Allergy Research & Education, End Allergies Together, Allergenis, and Ukko Pharma; has research sponsorship by Novartis, Sanofi, Astellas, and Nestle; and personal fees from Regeneron, Astrazeneca, ImmuneWorks, and Cour Pharmaceuticals. S. R. Durham reports grants from Immune Tolerance Network, NIAID, Regeneron, Biotech Tools, and ALK; nonfinancial support from ALK, during the conduct of the study; personal fees from Anergis, Circassia, Biomay, Merck, Allergy Therapeutics, ALK, med Update GmbH; and grants from Food Standards Agency, UK, and the National Institute of Health Research UK; outside of the submitted work. M. H. Shamji reports grants and personal fees from ASIT Biotech S.A., ALK, Regeneron, Merck, and Immune Tolerance Network, and personal fees from ASIT Biotech S.A., ALK, and Allergopharma, outside of the submitted work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 2
P. 663-676 - Febbraio 2021 Ritorno al numero
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