Hormonal regulation of ILC – HormonoILC

To assess the influence of AR-dependent signaling on ILC2, we will generate a genetic model that allows conditional deletion of the RA in lymphoid populations. This model will allow us to assess whether RA modifies the development of ILC2 as well as their number and location in tissues under homeostatic conditions and in models of allergic asthma. In parallel to unbiased exploratory methods, we wish to test, among other candidates, the role of KLRG1 in the inhibitory effect of androgens on ILC2. Indeed, we could show that the expression of KLRG1, a putative checkpoint inhibitor of ILC2, is increased by AR signalling in ILC2.

We have generated AR-deficient mouse model in the lymphoid compartment and have started its characterisation. In the absence of AR in ILC2, sex bias is no longer observed, either in homeostatic or inflammatory conditions. With this model now in our hands, we will now be able to assess the impact of AR deletion on the development of ILC2 and on their maintenance/localisation in the periphery. Regarding the role of KLRG1, we were able to exclude that KLRG1 is required for the inhibitory effect of androgens in acute asthma models. KLRG1 deficiency does not alter the number or the ability to produce cytokines in either male or female mice (Blanquart et al., 2022).

This work should allow help us identify not only the mechanisms behind sex bias in immunity, but also, more globally, to identify mechanisms behind the regulation of ILC2. As a result of this project, we plan to evaluate whether, as in mice, androgens regulate ILC2 in humans.

Targeting androgen signaling in ILC2s protects from IL-33-driven lung inflammation, independently of KLRG1.
Blanquart E, Mandonnet A, Mars M, Cenac C, Anesi N, Mercier P, Audouard C, Roga S, Serrano de Almeida G, Bevan CL, Girard JP, Pelletier L, Laffont S*, Guéry JC*. J Allergy Clin Immunol. 2022 Jan.
* co-last, co-corresponding.
www.jacionline.org/article/S0091-6749(21)00725-9/fulltext

While sex differences in susceptibility to infections, allergy or autoimmune diseases are well documented, the underlying biological mechanisms are not sufficiently studied. At the onset of adolescence, asthma becomes less prevalent in men than in women, suggesting a protective role of male sex hormones. Based on the crucial role of group 2 innate lymphoid cells (ILC2) in the induction of airway inflammation, we made the hypothesis that ILC2 could be influenced by sex hormones. We could demonstrate for the first time that androgen, via the activation of its receptor AR (androgen receptor) acts as a powerful negative regulator of ILC2 development and expansion. In this proposal, we will determine the molecular mechanisms behind these observations. Our project will help to characterize new molecular mechanisms regulating ILC2 and will lead to a better understanding of the mechanisms responsible for sex-differences in immune responses.