scholarly journals A Non-redundant Role for T cell-derived IL-22 in Antibacterial Defense of Colonic Crypts

2021 ◽  
Author(s):  
Casey T. Weaver ◽  
Carlene L. Zindl ◽  
Steven J. Witte ◽  
Vincent A. Laufer ◽  
Min Gao ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Damage Control ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Bacterial Invasion ◽  
Intestinal Epithelial ◽  
Colonic Crypts ◽  
Protective Genes ◽  
Type 3

IL-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.

scholarly journals Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

2015 ◽  
Vol 212 (11) ◽  
pp. 1783-1791 ◽  
Author(s):  
Patricia Aparicio-Domingo ◽  
Monica Romera-Hernandez ◽  
Julien J. Karrich ◽  
Ferry Cornelissen ◽  
Natalie Papazian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tissue Damage ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Damage ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Intestinal Tissue ◽  
Mucosal Surfaces ◽  
Type 3

Disruption of the intestinal epithelial barrier allows bacterial translocation and predisposes to destructive inflammation. To ensure proper barrier composition, crypt-residing stem cells continuously proliferate and replenish all intestinal epithelial cells within days. As a consequence of this high mitotic activity, mucosal surfaces are frequently targeted by anticancer therapies, leading to dose-limiting side effects. The cellular mechanisms that control tissue protection and mucosal healing in response to intestinal damage remain poorly understood. Type 3 innate lymphoid cells (ILC3s) are regulators of homeostasis and tissue responses to infection at mucosal surfaces. We now demonstrate that ILC3s are required for epithelial activation and proliferation in response to small intestinal tissue damage induced by the chemotherapeutic agent methotrexate. Multiple subsets of ILC3s are activated after intestinal tissue damage, and in the absence of ILC3s, epithelial activation is lost, correlating with increased pathology and severe damage to the intestinal crypts. Using ILC3-deficient Lgr5 reporter mice, we show that maintenance of intestinal stem cells after damage is severely impaired in the absence of ILC3s or the ILC3 signature cytokine IL-22. These data unveil a novel function of ILC3s in limiting tissue damage by preserving tissue-specific stem cells.

scholarly journals Type 3 innate lymphoid cells maintain intestinal epithelial stem cells after tissue damage

2015 ◽  
Vol 210 (7) ◽  
pp. 2107OIA193
Author(s):  
Patricia Aparicio-Domingo ◽  
Monica Romera-Hernandez ◽  
Julien J. Karrich ◽  
Ferry Cornelissen ◽  
Natalie Papazian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tissue Damage ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Intestinal Epithelial ◽  
Epithelial Stem Cells ◽  
Type 3

scholarly journals Store-Operated Calcium Entry Controls Innate and Adaptive Immune Cell Function in Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Marilena Letizia ◽  
Ulrike Kaufmann ◽  
Yin-Hu Wang ◽  
Lorenz Gerbeth ◽  
Annegret Sand ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Bowel Disease ◽  
Clinical Course ◽  
Lymphoid Cells ◽  
Inflammatory Bowel ◽  
The Impact ◽  
Pharmacologic Inhibition

AbstractObjectiveInflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses and constitutes a major clinical challenge in need of new treatment modalities to improve patient care. Store-operated Ca2+ entry (SOCE) is the predominant Ca2+ influx pathway in T cells and other immune cells, regulating many of their functional properties. It is currently unknown whether the pharmacologic blockade of SOCE represents a suitable drug-target for IBD treatment.DesignUsing mass and flow cytometry the effects of SOCE inhibition on lamina propria (LP) immune cells of patients with ulcerative colitis (UC) and Crohn’s disease (CD) were investigated. Primary organoid cultures served to study the impact of SOCE inhibition on the function, differentiation and survival of intestinal epithelial cells (IEC). T cell transfer models of colitis were applied to examine how the genetic or pharmacologic ablation of SOCE affects the clinical course of IBD in mice.ResultsWe observed that the LP of IBD patients is characterized by an enrichment of innate lymphoid cells (ILC), CD4+ and CD8+ effector- as well as T regulatory cells producing IL-17 and TNFα. The pharmacologic inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17, TNFα and IFNγ by human colonic T cells and ILC, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, without affecting the viability, differentiation and function of primary IEC. T cell-specific genetic deletion of the SOCE signaling components Orai1, Stim1 or Stim2 revealed that the magnitude of SOCE correlates with the function of T cells and intestinal inflammation in mice. Moreover, the pharmacologic inhibition of SOCE alleviated the clinical course of colitic mice.ConclusionOur data suggest that SOCE inhibition may serve as a new pharmacologic strategy for treating IBD.

scholarly journals IMMU-20. SINGLE-CELL RNASEQ OF TUMOR INFILTRATING IMMUNE CELLS FROM NEOADJUVANT ANTI-PD1 TREATED GBM PATIENTS REVEALS GLOBAL TRANSCRIPTIONAL CHANGES AND IMMUNOSUPPRESSIVE ADAPTIVE RESPONSES BY MYELOID CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii109
Author(s):  
Alexander Lee ◽  
Aaron Mochizuki ◽  
Frances Chow ◽  
Jeremy Reynoso ◽  
Joey Orpilla ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Trajectory Analysis ◽  
Myeloid Cells ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
Transcriptional Changes

Abstract INTRODUCTION Neoadjuvant anti-PD1 therapy (neo-aPD1) was previously shown to significantly increase the survival of recurrent glioblastoma patients in a small randomized clinical trial. However, neo-aPD1 alone was not curative so defining the limitations of neo-aPD1 and discovering where other immunotherapies can be used alongside neo-aPD1 is needed. METHODS To understand how immune cells in the tumor microenvironment change with neo-aPD1, we used single-cell RNAsequencing to analyze cells from 27 glioma patients (n = 105,143 cells) of which 9 patients had received neo-aPD1 (n = 33,325 cells). Using unsupervised clustering and pseudotime trajectory analysis, we characterized the transcriptional changes within immune cells and how these populations changed with therapy. RESULTS We defined the immune landscape of the glioblastoma tumor microenvironment. Compared to no immunotherapy treatment, neo-aPD1 significantly increased the ratio of T cells to myelo-monocytic cells and led to significant increases in the effector and memory T cell populations but no significant changes in myeloid cell composition. Our differential gene expression analysis of the myeloid compartment showed significant increases in interferon-γ-responsive genes and down-regulation of genes associated with M2 macrophages and MDSCs, suggestive that neo-aPD1 influences the transcriptional profile of myeloid cells in the tumor microenvironment. Interestingly, our psuedotime trajectory analysis showed that neo-aPD1 was associated with cells expressing both lymphoid and myeloid-related genes, which we theorized to actually be lymphoid-myeloid cell doublets caused by increased interactions between myeloid and lymphoid cells. These doublets were highly enriched in MHC I and II, macrophage, T cell, and T cell activation and exhaustion genes indicating that neo-aPD1 may result in some adaptive immunosuppressive mechanism by increasing these interactions. This could explain why neo-aPD1 alone is not curative for glioblastoma patients. CONCLUSIONS In total, neoadjuvant anti-PD1 therapy enhances effector T cell activity, but may concomitantly induce adaptive resistance mediated by myeloid cells in glioblastoma.

scholarly journals Transient Suppression of Shigella flexneri Type 3 Secretion by a Protective O-Antigen-Specific Monoclonal IgA

mBio ◽  
2011 ◽  
Vol 2 (3) ◽  
Author(s):  
Stephen J. Forbes ◽  
Tia Bumpus ◽  
Elizabeth A. McCarthy ◽  
Blaise Corthésy ◽  
Nicholas J. Mantis
Keyword(s):  
Epithelial Cells ◽  
Mucosal Immunity ◽  
Intestinal Epithelial Cells ◽  
Shigella Flexneri ◽  
Secretory Iga ◽  
Bacterial Invasion ◽  
Intestinal Epithelial ◽  
Content Type ◽  
O Antigen ◽  
Type 3

ABSTRACTMucosal immunity to the enteric pathogenShigella flexneriis mediated by secretory IgA (S-IgA) antibodies directed against the O-antigen (O-Ag) side chain of lipopolysaccharide. While secretory antibodies against the O-Ag are known to prevent bacterial invasion of the intestinal epithelium, the mechanisms by which this occurs are not fully understood. In this study, we report that the binding of a murine monoclonal IgA (IgAC5) to the O-Ag ofS. flexneriserotype 5a suppresses activity of the type 3 secretion (T3S) system, which is necessary forS. flexnerito gain entry into intestinal epithelial cells. IgAC5’s effects on the T3S were rapid (5 to 15 min) and were coincident with a partial reduction in the bacterial membrane potential and a decrease in intracellular ATP levels. Activity of the T3S system returned to normal levels 45 to 90 min following antibody treatment, demonstrating that IgAC5’s effects were transient. Nonetheless, these data suggest a model in which the association of IgA with the O-Ag ofS. flexneripartially de-energizes the T3S system and temporarily renders the bacterium incapable of invading intestinal epithelial cells.IMPORTANCESecretory IgA (S-IgA) serves as the first line of defense against enteric infections. However, despite its well-recognized role in mucosal immunity, relatively little is known at the molecular level about how this class of antibody functions to prevent pathogenic bacteria from penetrating the epithelial barrier. It is generally assumed that S-IgA functions primarily by “immune exclusion,” a phenomenon in which the antibody binds to microbial surface antigens and thereby promotes bacterial agglutination, entrapment in mucus, and physical clearance from the gastrointestinal tract via peristalsis. The results of the present study suggest that in addition to serving as a physical barrier, S-IgA may have a direct impact on the ability of microbial pathogens to secrete virulence factors required for invasion of intestinal epithelial cells.

scholarly journals The Role of Human γδ T Cells in Anti-Tumor Immunity and Their Potential for Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1206 ◽  
Author(s):  
Yuxia Liu ◽  
Cai Zhang
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
T Cell Receptors ◽  
Γδ T Cells ◽  
Immune Defense ◽  
Cell Receptors

γδ T cells are a distinct subset of T cells whose T cell receptors consist of γ chains and δ chains, different from conventional αβ T cells. γδ T cells are considered as a member of the innate immunity because of their non-MHC restricted antigen recognition, rapid response to invading pathogens and sense early changes of malignant cells. Upon activation, they can further promote the activation of adaptive immune cells, such as T cells and B cells, by secreting various cytokines. Thus, γδ T cells are regarded as a bridge between innate immunity and acquired immunity. γδ T cells are involved in a variety of immune response processes, including immune defense and immune surveillance against infection and tumorigenesis. γδ T cells recognize multiple tumor-associated antigens or molecules in T cell receptors (TCRs)-dependent and natural killer cell receptors (NKRs)-dependent ways. γδ T cells not only display a direct killing capacity on a variety of tumors, but also exert anti-tumor immune responses indirectly by facilitating the function of other immune cells, such as dendritic cells (DCs), B cells and CD8+ T cells. In this review, we summarize the major subpopulations, the tumor recognition mechanisms, and the anti-tumor effects of human γδ T cells, particularly the potential of γδ T cells for cancer immunotherapy.

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

2021 ◽  
Vol 8 ◽  
Author(s):  
Anja Schulz-Kuhnt ◽  
Markus F. Neurath ◽  
Stefan Wirtz ◽  
Imke Atreya
Keyword(s):  
Epithelial Cell ◽  
Immune Cells ◽  
Inflammatory Bowel Diseases ◽  
Innate Lymphoid Cells ◽  
Experimental Models ◽  
Lymphoid Cells ◽  
Intestinal Epithelial ◽  
Epithelial Integrity ◽  
Bowel Diseases ◽  
Inflammatory Bowel

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.

scholarly journals Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens

2014 ◽  
Vol 211 (9) ◽  
pp. 1723-1731 ◽  
Author(s):  
Theresa L. Geiger ◽  
Michael C. Abt ◽  
Georg Gasteiger ◽  
Matthew A. Firth ◽  
Margaret H. O’Connor ◽  
...  
Keyword(s):  
Critical Role ◽  
Innate Lymphoid Cells ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Bzip Transcription Factor ◽  
Host Protection ◽  
Intestinal Pathogens ◽  
And Function ◽  
Type 3 ◽  
Deficient Mice

The bZIP transcription factor Nfil3 (also known as E4BP4) is required for the development of natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s). We find that Nfil3 plays a critical role in the development of other mucosal tissue-associated innate lymphocytes. Type 3 ILCs (ILC3s), including lymphoid tissue inducer (LTi)–like cells, are severely diminished in both numbers and function in Nfil3-deficient mice. Using mixed bone marrow chimeric mice, we demonstrate that Nfil3 is critical for normal development of gut-associated ILC3s in a cell-intrinsic manner. Furthermore, Nfil3 deficiency severely compromises intestinal innate immune defense against acute bacterial infection with Citrobacter rodentium and Clostridium difficile. Nfil3 deficiency resulted in a loss of the recently identified ILC precursor, yet conditional ablation of Nfil3 in the NKp46+ ILC3 subset did not perturb ILC3 numbers, suggesting that Nfil3 is required early during ILC3 development but not for lineage maintenance. Lastly, a marked defect in type 2 ILCs (ILC2s) was also observed in the lungs and visceral adipose tissue of Nfil3-deficient mice, revealing a general requirement for Nfil3 in the development of all ILC lineages.

scholarly journals Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 Induce the Expression of the REG3 Family in the Small Intestine of Mice via the Stimulation of Dendritic Cells and Type 3 Innate Lymphoid Cells

Nutrients ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2998 ◽  
Author(s):  
Kyosuke Kobayashi ◽  
Yoshiko Honme ◽  
Toshihiro Sashihara
Keyword(s):  
Small Intestine ◽  
Immune Cells ◽  
Intestinal Barrier ◽  
Streptococcus Thermophilus ◽  
Lymphoid Cells ◽  
Lactobacillus Delbrueckii ◽  
Intestinal Barrier Function ◽  
Small Intestinal ◽  
Type 3 ◽  
Lactobacillus Delbrueckii Subsp

Accumulating evidence clarifies that intestinal barrier function, for example, by the mucus layer, antimicrobial peptides, immune systems, and epithelial tight junctions, plays crucial roles in maintaining our health. We reported previously that yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 induced the gene expression of the regenerating family member 3 (REG3) family, which encodes antimicrobial peptides in the small intestine, although it was unclear how the yogurt activated the intestinal cells related to it. Here, we evaluated the cytokine production from the intestinal immune cells stimulated by these strains in vitro and in vivo to elucidate the mechanism for the induction of the REG3 family by the yogurt. The results showed that stimulation by both strains induced interleukin (IL)-23 production from bone marrow-derived dendritic cells (DCs) and IL-22 production from small intestinal lamina propria (LP) cells. In addition, oral administration of these strains to mice increased IL-23p19+ LPDCs and IL-22+ type 3 innate lymphoid cells and induced the expression of Reg3g in small intestinal tissue. Moreover, we showed that the activities for the induction of IL-23 by DCs were strain dependent on L. bulgaricus and S. thermophilus and that S. thermophilus 1131, which is the predominant species in the yogurt, exhibited relatively higher activity compared to the other strains of S. thermophilus. Our findings suggested that these yogurt starter strains, L. bulgaricus 2038 and S. thermophilus 1131, have the potential to maintain and improve intestinal barrier function by stimulating immune cells in the LP.

Sign in / Sign up

Export Citation Format

Share Document