ILC2 Suppression by Regulatory T Cells Attenuates Airway Hyperreactivity and Requires ICOS:ICOS-Ligand Interaction

Abstract

Background

Atopic diseases including asthma exacerbate type 2 immune responses and involve a number of immune cell types, including regulatory T cells (Tregs) and the emerging group 2 innate lymphoid cells (ILC2s). While ILC2s are potent producers of type 2 cytokines, the regulation of ILC2 activation and function is not well understood.

Objective

In the present study, we evaluate for the first time how Tregs interact with pulmonary ILC2s and control their function.

Methods

ILC2s and Tregs were evaluated using in vitro suppression assays, cell-contact assays, and gene expression panels. Also, human ILC2s and Tregs were adoptively transferred into NOD SCID gamma-C deficient (NSG) mice, which were given isotype or anti-ICOS-L antibodies, then challenged with IL-33 and assessed for AHR.

Results

We show that induced Tregs (iTregs), but not natural Tregs (nTregs), effectively suppress the production of ILC2-driven, pro-inflammatory cytokines IL-5 and IL-13, both in vitro and in vivo. Mechanistically, our data reveal the necessity of Inducible T cell Costimulator (ICOS):ICOS-Ligand cell contact for Treg-mediated ILC2 suppression, alongside suppressive cytokines TGF-β and IL-10. Using a translational approach, we then demonstrate that human iTregs suppress syngeneic human ILC2s via ICOS-L to control airway inflammation in a humanized ILC2 mouse model.

Conclusion

These findings suggest that peripheral expansion of induced Tregs may serve as a promising therapeutic target against ILC2-dependent asthma.

Capsule summary

ICOS-L on ILC2s is required for Treg mediated suppression in asthma.