Type 3 Innate Lymphoid Cells Direct Goblet Cell Differentiation via the LT–LTβR Pathway during<i>Listeria</i>Infection

Pian, Yaya; Chai, Qian; Ren, Boyang; Wang, Yue; Lv, Mengjie; Qiu, Ju; Zhu, Mingzhao

doi:10.4049/jimmunol.2000197

Cited by 15 publications

(19 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-22 secretion by NKp44 + ILC3 is activated after food intake (6,7), sensing danger signals (8,9) as well as changes in cytokine milieu (3,10). Furthermore, NKp44 + ILC3s express neuroregulatory receptors enabling direct interactions with glial cells (11), but also interact with the microbiome (12) and goblet cells (13). The secreted IL-22 acts upon epithelial cells and intestinal stem cells (ISCs), both expressing the IL-22 receptor (IL-22R) (14), which is absent on cells from the hematopoietic lineage.…”

Section: Introductionmentioning

confidence: 99%

Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche

et al. 2021

View full text Add to dashboard Cite

Innate lymphoid cells (ILCs) and in particular ILC3s have been described to be vital for mucosal barrier functions and homeostasis within the gastrointestinal (GI) tract. Importantly, IL-22-secreting ILC3 have been implicated in the control of inflammatory bowel disease (IBD) and were shown to reduce the incidence of graft-versus-host disease (GvHD) as well as the risk of transplant rejection. Unfortunately, IL-22-secreting ILC3 are primarily located in mucosal tissues and are not found within the circulation, making access to them in humans challenging. On this account, there is a growing desire for clinically applicable protocols for in vitro generation of effector ILC3. Here, we present an approach for faithful generation of functionally competent human ILC3s from cord blood-derived CD34+ hematopoietic progenitors on layers of human mesenchymal stem cells (MSCs) generated in good manufacturing practice (GMP) quality. The in vitro-generated ILC3s phenotypically, functionally, and transcriptionally resemble bona fide tissue ILC3 with high expression of the transcription factors (TF) RorγT, AHR, and ID2, as well as the surface receptors CD117, CD56, and NKp44. Importantly, the majority of ILC3 belonged to the desired effector subtype with high IL-22 and low IL-17 production. The protocol thus combines the advantages of avoiding xenogeneic components, which were necessary in previous protocols, with a high propensity for generation of IL-22-producing ILC3. The present approach is suitable for the generation of large amounts of ILC3 in an all-human system, which could facilitate development of clinical strategies for ILC3-based therapy in inflammatory diseases and cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Type 3 Innate Lymphoid Cells (ILC3s) promotes goblet cell differentiation and the expression of MUC2 through the lymphotoxin (LT)-LTβR pathway during intestinal listeria infection. 10 , 97 DCs such as macrophages and dendritic cells provide processed, phagocytosed antigens for activating and instructing naïve CD4+ T cells to convert to type 2 helper (Th2) cells. 98 , 99 These cells are essential for the immune response against extracellular parasites and intracellular pathogens, resulting in the increased secretion of cytokines like IL-13, IL-9, IL-5, and IL-4.…”

Section: Immune Regulation Of Goblet Cell Functionmentioning

confidence: 99%

“… 4 The absence of or any defect in the mucus layer allows a large number of bacteria to make contact with the epithelial cells, triggering an excessive immune response in the host, 5 leading to colitis in mice. 6 Various intestinal infections resulting from parasites, 7 , 8 viruses, 9 and bacteria 10 modify the production of mucin and goblet cells, demonstrating the importance of the mucus layer in separating the luminal contents from the epithelium. However, the critical function of the mucus layer and goblet cells in host defense has not received adequate attention.…”

Section: Introductionmentioning

confidence: 99%

Role of Goblet Cells in Intestinal Barrier and Mucosal Immunity

Yang¹,

Yu²

2021

JIR

161

View full text Add to dashboard Cite

Goblet cells and the mucus they secrete serve as an important barrier, preventing pathogens from invading the mucosa to cause intestinal inflammation. The perspective regarding goblet cells and mucus has changed, with current evidence suggesting that they are not passive but play a positive role in maintaining intestinal tract immunity and mucosal homeostasis. Goblet cells could obtain luminal antigens, presenting them to the underlying antigen-presenting cells (APCs) that induces adaptive immune responses. Various immunomodulatory factors can promote the differentiation and maturation of goblet cells, and the secretion of mucin. The abnormal proliferation and differentiation of goblet cells, as well as the deficiency synthesis and secretion of mucins, result in intestinal mucosal barrier dysfunction. This review provides an extensive outline of the signaling pathways that regulate goblet cell proliferation and differentiation and control mucins synthesis and secretion to elucidate how altering these pathways affects goblet functionality. Furthermore, the interaction between mucins and goblet cells in intestinal mucosal immunology is described. Therefore, the contribution of goblet cells and mucus in promoting gut defense and homeostasis is illustrated, while clarifying the regulatory mechanisms involved may allow the development of new therapeutic strategies for intestinal disorders.

show abstract

“…During intestinal Listeria monocytogenes infection, ILC3s appeared as important inducers of goblet cell differentiation and function, enabling efficient bacteria control. Making use of an in vitro coculture transwell assay, the necessity of a direct interaction of lymphotoxin-secreting RORγt + cells and lymphotoxin-β receptor (LTβR) expressing IECs for efficient Muc2 induction was shown, with ILC3s being suggested as lymphotoxin-expressing interaction partner (87). Though the role of direct ILC3-goblet cell interactions have not been described in IBD yet, a prominent function of IL-22 has been confirmed in the inflamed gut (Figure 2).…”

Section: Goblet Cells-ilcsmentioning

confidence: 99%

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

2021

View full text Add to dashboard Cite

The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD.

show abstract

Type 3 Innate Lymphoid Cells Direct Goblet Cell Differentiation via the LT–LTβR Pathway duringListeriaInfection

Cited by 15 publications

References 60 publications

Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche

Efficient In Vitro Generation of IL-22-Secreting ILC3 From CD34+ Hematopoietic Progenitors in a Human Mesenchymal Stem Cell Niche

Role of Goblet Cells in Intestinal Barrier and Mucosal Immunity

Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

Contact Info

Product

Resources

About