TSLP and IL-33 distinctively modulate the allergic response by differentially modulating Th2 cells and ILC2s

Abstract

Abstract Alarmins are endogenous chemotactic or immune-activating proteins released after cell injury or immune activation, and these include thymic stromal lymphopoietin (TSLP) and IL-33. Mice lacking these cytokines exhibit defective type 2 responses, but there is controversy regarding the roles of these cytokines in allergic responses in vivo. Here, we demonstrate that the nature of the allergic response is dictated by the alarmin. Mice lacking IL-33 were resistant to pulmonary inflammation induced by papain, but they exhibited normal OVA-induced allergic inflammation. In contrast, mice lacking either TSLP or TSLPR had significantly lower pulmonary inflammation in response to OVA challenge but responded normally to papain. Moreover, while intranasal papain challenge rapidly induced the release of IL-33, OVA challenge predominantly released TSLP. Steady-state pulmonary ILC2s were activated in response to IL-33, and correspondingly, Il33 KO mice showed a similar defect in effector Th2 generation to that observed in animals lacking ILC2s. In contrast to IL-33, TSLP did not activate steady-state ILC2s. Instead, conditional deletion of TSLPR in T cells hampered Th2 cell generation in the OVA-induced asthma model, but these mice responded normally to papain. These data demonstrate that Th2 cells rely on IL-33-stimulated ILC2s, whereas in the OVA-induced asthma model, TSLP acts on Th2 cells to promote type 2 responses. Thus, TSLP and IL-33 are both alarmins, but they have distinctive effects on allergic responses based on their different release kinetics and on their differential actions on Th2 cells versus ILC2s. These findings indicate approaches to selectively target different allergic responses, with potential translational impact. This research was supported by the Intramural Research Programs of NIAID and NHLBI, NIH.