An exhausted phenotype of T_H 2 cells is primed by allergen exposure, but not reinforced by allergen-specific immunotherapy.

Abstract

Studies show that proallergic T_H 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. OVA-sensitized C57BL/6J mice were challenged and treated with OVA, and the development of exhaustion in local and systemic T_H 2 cells was analyzed. In patients, the expression of exhaustion-associated surface markers on T_H 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. The exhaustion-associated surface markers CTLA-4 and PD-1 were significantly upregulated on T_H 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 T_H 2 cells. Similarly, CTLA-4 and PD-1 expression was enhanced on T_H 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 T_H 2 population expressing both markers that decreased during up-dosing but persisted long term during the maintenance phase. This study shows that allergen exposure promotes CTLA-4 and PD-1 expression on T_H 2 cells and that the dynamic change in frequencies of exhausted T_H 2 cells exhibits a differential pattern during the up-dosing versus the maintenance phases of AIT.