IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection

Abstract

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines.

Developments allergy in 2019 through the eyes of clinical and experimental allergy, part I mechanisms

“…The cytokine, IL-17, is a potent driver of neutrophil recruitment and plays a complex role in both initiation and suppressing type 2 inflammatory responses, such as those seen in allergic asthma. 57 A study by de-Oliverira and colleagues investigated the rules governing the localization of IL-17-producing gamma-delta T cells in the airways of mice. 58 Specifically, the authors found that offspring of mice that had been immunized with an antigen, and subsequently developed a specific IgG response, exhibited a reduced number of IL-17 producing gamma-delta cells in the airways.…”

Remote tissue immune priming in allergic disease

“…This is in line with a recent observation where intestinal helminth infection was shown to influence lung responses (in the absence of a lung challenge) through IL-17mediated dampening of IFNγ, which consequently enhanced Th2 responses. 6…”

IL-17A moonlighting in lung type 2 immunity

“…In this issue of Mucosal Immunology, Ajendra et al reveal previously unrecognized ways that IL-17A "multi-tasks" in the lung, to both promote and inhibit Type 2 inflammation, depending on timing and the surrounding inflammatory milieu, using the Nippostrongylus brasiliensis helminth infection model in mice. 1 N. brasiliensis is a hookworm-like parasite that after infecting its host through the skin, migrates quickly through the lung between days 1 and 3 post-infection inducing damage and inflammation, before reaching its final destination, the intestines by days 5-7. The authors show that in this setting, IL-17A expression is rapidly induced in γδ T cells in the lung at day 2, which acts to suppress the production of IFNγ by T cells and NK cells, facilitating the induction of a type 2 response while the helminth passes through the lung.…”

“…Overall, Ajendra et al 1 presents an exciting new model in which helminth infection-driven IL-17A is central for both the initiation of a Type 2 response, and its subsequent inhibition to help prevent chronic Type 2 inflammation and tissue damage. Suppression of IFNγ expression in the lung appears to be a critical intermediate event, and appears to be a tissue-specific phenomenon.…”

“…During later infection (day 6), IL-17A acts instead to suppress this Type 2 response, preventing excessive inflammation and tissue damage. 1 The source of IL-17A and the mechanism of suppression of Type 2 immunity remain unclear. This IL-17A-dependent molecular switch adds to previously characterized mechanisms of how Type 2 immunity in the lung is regulated during helminth infections, including the similarly multitasking factor RELMα, produced by alternatively activated macrophages (AAMac), which can both promote early Type 2 responses to helminths, 4 and act to suppress these responses at later times.…”