An exhausted phenotype of T<sub>H</sub>2 cells is primed by allergen exposure, but not reinforced by allergen‐specific immunotherapy
Shu‐Hung Wang, Ulrich M. Zissler, Maren Buettner, Sonja Heine, Alexander Heldner, Sebastian Kotz, Lisa Pechtold, Josephine Kau, Mirjam Plaschke, Julia T. Ullmann, Ferdinand Guerth, Madlen Oelsner, Francesca Alessandrini, Simon Blank, Adam Chaker, Carsten B. Schmidt‐Weber, Constanze A. Jakwerth
Abstract
Abstract Background 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. Methods 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. Results 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. Conclusions 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.