Author:
Zindl Carlene L.,Witte Steven J.,Laufer Vincent A.,Gao Min,Yue Zongliang,Silberger Daniel J.,Harbour Stacey N.,Singer Jeffrey R.,Pham Duy,Moseley Carson E.,Cai Baiyi,Turner Henrietta,Lund Fran E.,Vallance Bruce A.,Rosenberg Alexander F.,Chen Jake Y.,Hatton Robin T.,Weaver Casey T.
Abstract
SummaryIL-22 is a key cytokine in immune defense against pathogens at barrier sites. In response to enteric attaching and effacing bacteria, IL-22 produced by type 3 innate lymphoid cells (ILC3s) is thought to be important early for induction of antimicrobial peptides (AMPs) that protect intestinal epithelial cells (IECs) in advance of T cell-derived IL-22 that arises later. Yet, the basis for a requirement for both innate and adaptive IL-22–producing immune cells in protecting the intestinal mucosa is unknown. Here, using novel mice that both report IL-22 expression and can be targeted for its lineage-specific deletion, we show that mice with deficiency of IL-22 targeted to innate immune cells, including ILC3s, have impaired STAT3 activation of surface colonic IECs colonized by bacteria early in infection. In contrast, mice with IL-22 deficiency limited to T cells have complete loss of STAT3 activation in IECs lining colonic crypts and fail to protect the crypts from bacterial invasion late despite ongoing production of IL-22 from ILC3s. T cell-derived IL-22 is required for upregulation of many host-protective genes by crypt IECs, including those encoding AMPs, neutrophil-recruiting chemokines, and mucins and mucin-related molecules, while also restricting pro-inflammatory genes downstream of IFNγ and TNF signals. Thus, T cell-derived IL-22 is indispensable for antibacterial defense and damage control of intestinal crypts.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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