CISH constrains the tuft–ILC2 circuit to set epithelial and immune tone

Kotas, Maya E.; Mroz, Nicholas M.; Koga, Satoshi; Liang, Hong-Erh; Schroeder, Andrew; Ricardo-González, Roberto R.; Schneider, Christoph; Locksley, Richard M.

doi:10.1038/s41385-021-00430-6

Cited by 17 publications

(12 citation statements)

References 62 publications

(99 reference statements)

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“…There are factors that can limit this feed-forward loop. For example, the putative epithelial-intrinsic PGD 2 -CRTH2 axis counteracts the IL-13–induced epithelial response ( 32 ), and ILC2-expressed cytokine-inducible SH2-containing protein (CISH) blocks ILC2 activation, which in turn limits tuft cell expansion ( 33 ). Other competing cytokines can also affect this loop, as IL-22 inhibits IL-13–induced tuft cell responses ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

et al. 2022

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The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13–driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2–driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis . Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.

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Section: Discussionmentioning

confidence: 99%

BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

et al. 2022

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“…CIS also inhibits T cell receptor signaling (Palmer et al, 2015). Thus, CIS has also been shown to regulate additional immune cells including ILC2s (Kotas et al, 2021), CD4 + and CD8 + T cells (Palmer et al, 2015;Yang et al, 2013), neutrophils (Louis et al, 2020), and macrophages (Carow et al, 2017;E. et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Salmonella Typhimurium infection drives NK cell loss and conversion to ILC1-like cells, and CIS inhibition enhances antibacterial immunity

Souza-Fonseca-Guimarães

McCulloch

Rossi

et al. 2021

Preprint

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Immunotherapy has revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in tumor-resident T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation, and activation can be neutralized through the TGF-β immunosuppressive pathway by inducing plasticity of NK cells and differentiation into ILC1-like subsets. NK cells are also regulated through cytokine-inducible SH2-containing protein (CIS), which is induced by IL-15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise is cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti-bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1-like for the first time in the context of bacterial infection, however TGF-β signaling was curiously redundant in this plasticity. Future work should focus on identifying drivers of ILC1 plasticity and its functional implication in bacterial infection models. We further describe that CIS-deficient mice displayed enhanced pro-inflammatory function and dramatically enhanced anti-infection immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection.

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“…Cytokine-inducible SH2-containing protein (CISH) also negatively regulates ILC2s at homeostasis and during N . brasiliensis infection, as CISH restricts IL-25–dependent ILC2 activation [ 107 ]. Global or ILC2-specific CISH knockout also expedites N .…”

Section: Tuft Cells In Host–microbe Interactionsmentioning

confidence: 99%

“…Global or ILC2-specific CISH knockout also expedites N . brasiliensis expulsion and increases tuft cell numbers at early infection time points [ 107 ]. Perhaps N .…”

Section: Tuft Cells In Host–microbe Interactionsmentioning

confidence: 99%

Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces

Strine

Wilen

2022

PLoS Pathog

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Although tuft cells were discovered over 60 years ago, their functions have long been enigmatic, especially in human health. Nonetheless, tuft cells have recently emerged as key orchestrators of the host response to diverse microbial infections in the gut and airway. While tuft cells are epithelial in origin, they exhibit functions akin to immune cells and mediate important interkingdom interactions between the host and helminths, protists, viruses, and bacteria. With broad intra- and intertissue heterogeneity, tuft cells sense and respond to microbes with exquisite specificity. Tuft cells can recognize helminth and protist infection, driving a type 2 immune response to promote parasite expulsion. Tuft cells also serve as the primary physiologic target of persistent murine norovirus (MNV) and promote immune evasion. Recently, tuft cells were also shown to be infected by rotavirus. Other viral infections, such as influenza A virus, can induce tuft cell–dependent tissue repair. In the context of coinfection, tuft cells promote neurotropic flavivirus replication by dampening antiviral adaptive immune responses. Commensal and pathogenic bacteria can regulate tuft cell abundance and function and, in turn, tuft cells are implicated in modulating bacterial infiltration and mucosal barrier integrity. However, the contribution of tuft cells to microbial sensing in humans and their resulting effector responses are poorly characterized. Herein, we aim to provide a comprehensive overview of microbial activation of tuft cells with an emphasis on tuft cell heterogeneity and differences between mouse and human tuft cell biology as it pertains to human health and disease.

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CISH constrains the tuft–ILC2 circuit to set epithelial and immune tone

Cited by 17 publications

References 62 publications

BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

Salmonella Typhimurium infection drives NK cell loss and conversion to ILC1-like cells, and CIS inhibition enhances antibacterial immunity

Tuft cells are key mediators of interkingdom interactions at mucosal barrier surfaces

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