An exhausted phenotype of T H 2 cells is primed by allergen exposure, but not reinforced by allergen‐specific immunotherapy
| Autor: | Carsten Schmidt-Weber, Sebastian Kotz, Adam Chaker, Mirjam Plaschke, Shu-Hung Wang, Ferdinand Guerth, Sonja Heine, Alexander Heldner, Julia T Ullmann, Maren Buettner, Francesca Alessandrini, Ulrich M. Zissler, Lisa Pechtold, Constanze A. Jakwerth, Simon Blank, Josephine Kau, Madlen Oelsner |
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| Rok vydání: | 2021 |
| Předmět: |
education.field_of_study
Lung medicine.diagnostic_test business.industry medicine.medical_treatment Immunology Population Immunotherapy medicine.disease Peripheral blood mononuclear cell ddc Flow cytometry Ait Ctla-4 Pd-1 T Cell Exhaustion Proallergic Th2 medicine.anatomical_structure Downregulation and upregulation CTLA-4 medicine Immunology and Allergy education business Asthma |
| Zdroj: | Allergy 76, 2827-2839 (2021) |
| ISSN: | 1398-9995 0105-4538 |
| Popis: | BACKGROUND Studies show that proallergic TH 2 cells decrease after successful allergen-specific immunotherapy (AIT). It is likely that iatrogenic administration of allergens drives these cells to exhaustion due to chronic T-cell receptor stimulation. This study aimed to investigate the exhaustion of T cells in connection with allergen exposure during AIT in mice and two independent patient cohorts. METHODS OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic TH 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on TH 2 cells was evaluated using flow cytometry in a cross-sectional grass pollen allergy cohort with and without AIT. The treatment effect was further studied in PBMC collected from a prospective long-term AIT cohort. RESULTS The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on TH 2 cells upon OVA aerosol exposure in OVA-allergic compared to non-allergic mice. CTLA-4 and PD-1 decreased after AIT, in particular on the surface of local lung TH 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on TH 2 cells from patients with allergic rhinitis with an even stronger effect in those with concomitant asthma. Using an unbiased Louvain clustering analysis, we discovered a late-differentiated TH 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase. CONCLUSIONS This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on TH 2 cells and that the dynamic change in frequencies of exhausted TH 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT. |
| Databáze: | OpenAIRE |
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