Innate Lymphoid Cells Control Early Colonization Resistance against Intestinal Pathogens through Id2−dependent Regulation of Microbiota

Bacterial infections remain highly prevalent diseases in developing countries. Infections, especially those that are caused by antibiotic-resistant bacteria, cause high morbidity and mortality in hospitalized patients. Although most studies focus on innate and adaptive immune responses, recent publications suggest that pathogen colonization resistance could be dependent on direct inhibition by microbiota before innate and adaptive immune responses take place. However, it is unknown whether and how the host shapes the microbiota to mediate colonization resistance to pathogens. Innate lymphoid cells (ILCs) are newly defined immune cells that protect the host from various infections. Id2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice that delete Id2 in differentiated ILC3s, we observe that these mutant mice exhibit greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we show that the Id2-dependent early colonization resistance was through IL-22 mediated regulation of microbiota. We also demonstrated that, in addition to controlling the development and maintenance of ILC3s, Id2 regulated IL-22 production through an Ahr and IL23R pathway. We conclude that ILC3s can mediate immune surveillance that constantly maintains proper microbiota to mediate early colonization resistance through an Id2−dependent regulation of IL-22. Considering the difficulty to modify the microbiota in adult patients, our study suggests that a combination of immune molecule supplementation and microbiota transplantation may be a better approach to introduce a stable healthy microbial community.