Multiple-checkpoint inhibition of thymic stromal lymphopoietin-induced TH2 response by TH17-related cytokines

The interplay between allergy and autoimmunity has been a matter of long debate. Epidemiologic studies point to a decreased frequency of allergy in patients with autoimmune diseases. However, recent studies suggest that IL-17 and related cytokines, which play a central role in autoimmunity, might also promote allergy.

To address this controversy, we systematically studied the interactions between T(H)17-related cytokines and the thymic stromal lymphopoietin (TSLP)-mediated proallergic pathway.

We used human primary dendritic cells (DCs), T cells, and skin explants. A novel geometric representation and multivariate ANOVA were used to analyze the T(H) cytokine profile.

We show that IL-17A specifically inhibits TSLP production but increases proinflammatory IL-8 production in human skin explants exposed to TNF-α and IL-4. This inhibitory activity was confirmed in cultured skin explants of atopic dermatitis lesions. At the T-cell level, T(H)17-polarizing cytokines (IL-1β, IL-6, TGF-β, and IL-23) inhibited T(H)2 differentiation induced by TSLP-activated DCs. This led to a global dominance of a T(H)17-polarizing environment over TSLP-activated DCs, as revealed by clustering and computational analysis.

Our data indicate that T(H)17-related cytokines are negative regulators of the TSLP immune pathway. This might explain the decreased frequency of allergy in patients with autoimmunity and suggests new means of manipulating proallergic responses.