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

Background: 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. Objective: To address this controversy, we systematically studied the interactions between T(H)17-related cytokines and the thymic stromal lymphopoietin (TSLP)-mediated proallergic pathway. Methods: 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. Results: We show that IL-17A specifically inhibits TSLP production but increases proinflammatory IL-8 production in human skin explants exposed to TNF-alpha 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-1 beta, IL-6, TGF-beta, 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. Conclusions: 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. (J Allergy Clin Immunol 2012; 130:233-40.)