scholarly journals NLRP1B and NLRP3 control the host response following colonization by the commensal protist Tritrichomonas musculis.

2021 ◽  
Author(s):  
Pailin Chiaranunt ◽  
Kyle Burrows ◽  
Louis Ngai ◽  
Eric Y Cao ◽  
Helen Liang ◽  
...  
Keyword(s):  
Host Defense ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Host Response ◽  
Cell Activation ◽  
Intestinal Protozoa ◽  
Host Protection ◽  
Salmonella Infections ◽  
Immune Changes ◽  
Microbial Host

Commensal intestinal protozoa, unlike their pathogenic relatives, are neglected members of the mammalian microbiome. These microbes have a significant impact on host intestinal immune homeostasis, typically by elevating anti-microbial host defense. Tritrichomonas musculis (T. mu), a protozoan gut commensal, strengthens the intestinal host defense against enteric Salmonella infections through Asc- and Il1r1-dependent Th1 and Th17 cell activation. However, the underlying inflammasomes mediating this effect remain unknown. Here, we report that colonization with T. mu results in an increase in luminal extracellular ATP, elevated levels of IL-1b, and increased numbers of IL-18 receptor-expressing Th1 and Th17 cells in the colon. Mice deficient in either Nlrp1b or Nlrp3 failed to display these protozoan-driven immune changes and lost resistance to enteric Salmonella infections even in the presence of T. mu. These findings demonstrate that T. mu-mediated host protection requires sensors of extra and intracellular ATP to confer full resistance to enteric Salmonella infections.

scholarly journals Th17 Cell Response inSOD1G93AMice following Motor Nerve Injury

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Allen Ni ◽  
Tao Yang ◽  
Nichole A. Mesnard-Hoaglin ◽  
Rafael Gutierrez ◽  
Evan B. Stubbs ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Nerve Injury ◽  
T Cell Activation ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Motor Nerve ◽  
Presymptomatic Stage ◽  
Increased Risk

An increased risk of ALS has been reported for veterans, varsity athletes, and professional football players. The mechanism underlying the increased risk in these populations has not been identified; however, it has been proposed that motor nerve injury may trigger immune responses which, in turn, can accelerate the progression of ALS. Accumulating evidence indicates that abnormal immune reactions and inflammation are involved in the pathogenesis of ALS, but the specific immune cells involved have not been clearly defined. To understand how nerve injury and immune responses may contribute to ALS development, we investigated responses of CD4+T cell after facial motor nerve axotomy (FNA) at a presymptomatic stage in a transgenic mouse model of ALS (B6SJLSOD1G93A).SOD1G93Amice, compared with WT mice, displayed an increase in the basal activation state of CD4+T cells and higher frequency of Th17 cells, which were further enhanced by FNA. In conclusion,SOD1G93Amice exhibit abnormal CD4+T cell activation with increased levels of Th17 cells prior to the onset of neurological symptoms. Motor nerve injury exacerbates Th17 cell responses and may contribute to the development of ALS, especially in those who carry genetic susceptibility to this disease.

scholarly journals Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

2014 ◽  
Vol 82 (5) ◽  
pp. 2106-2114 ◽  
Author(s):  
Chiung-Yu Hung ◽  
María del Pilar Jiménez-Alzate ◽  
Angel Gonzalez ◽  
Marcel Wüthrich ◽  
Bruce S. Klein ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Pulmonary Infection ◽  
Interleukin 1 ◽  
Signal Pathways ◽  
Toll Like Receptor ◽  
Content Type ◽  
Toll Like Receptor 2

ABSTRACTInterleukin-17A (IL-17A)-producing CD4+T helper (Th17) cells have been shown to be essential for defense against pulmonary infection withCoccidioidesspecies. However, we have just begun to identify the required pattern recognition receptors and understand the signal pathways that lead to Th17 cell activation after fungal infection. We previously reported thatCard9−/−mice vaccinated with formalin-killed spherules failed to acquire resistance toCoccidioidesinfection. Here, we report that bothMyD88−/−andCard9−/−mice immunized with a live, attenuated vaccine also fail to acquire protective immunity to this respiratory disease. LikeCard9−/−mice, vaccinatedMyD88−/−mice revealed a significant reduction in numbers of both Th17 and Th1 cells in their lungs afterCoccidioidesinfection. Both Toll-like receptor 2 (TLR2) and IL-1 receptor type 1 (IL-1r1) upstream of MyD88 have been implicated in Th17 cell differentiation. Surprisingly, vaccinatedTLR2−/−and wild-type (WT) mice showed similar outcomes after pulmonary infection withCoccidioides, while vaccinatedIL-1r1−/−mice revealed a significant reduction in the number of Th17 cells in their infected lungs compared to WT mice. Thus, activation of both IL-1r1/MyD88- and Card9-mediated Th17 immunity is essential for protection againstCoccidioidesinfection. Our data also reveal that the numbers of Th17 cells were reduced inIL-1r1−/−mice to a lesser extent than inMyD88−/−mice, raising the possibility that other TLRs are involved in MyD88-dependent Th17 immunity to coccidioidomycosis. An antimicrobial action of Th17 cells is to promote early recruitment of neutrophils to infection sites. Our data revealed that neutrophils are required for vaccine immunity to this respiratory disease.

scholarly journals HuR Plays a Positive Role to Strengthen the Signaling Pathways of CD4+ T Cell Activation and Th17 Cell Differentiation

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Shiguang Yu ◽  
Morgan Tripod ◽  
Ulus Atasoy ◽  
Jing Chen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Signaling Pathways ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Th17 Cell Differentiation

After antigen and/or different cytokine stimulation, CD4+ T cells activated and differentiated into distinct T helper (Th) cells via differential T cell signaling pathways. Transcriptional regulation of the activation and differentiation of naïve CD4+ T cells into distinct lineage Th cells such as Th17 cells has been fully studied. However, the role of RNA-binding protein HuR in the signaling pathways of their activation and differentiation has not been well characterized. Here, we used HuR conditional knockout (HuR KO) CD4+ T cells to study mechanisms underlying HuR regulation of T cell activation and differentiation through distinct signaling pathways. Our work showed that, mechanistically, HuR positively promoted CD3g expression by binding its mRNA and enhanced the expression of downstream adaptor Zap70 and Malt1 in activated CD4+ T cells. Compared to WT Th0 cells, HuR KO Th0 cells with reduced Bcl-2 expression are much more susceptible to apoptosis than WT Th0 cells. We also found that HuR stabilized IL-6Rα mRNA and promoted IL-6Rα protein expression, thereby upregulating its downstream phosphorylation of Jak1 and Stat3 and increased level of phosphorylation of IκBα to facilitate Th17 cell differentiation. However, knockout of HuR increased IL-22 production in Th17 cells, which was due to HuR deficiency in reducing IL-22 transcription repressor c-Maf expression. These results highlight the importance of HuR in TCR signaling and IL-6/IL-6R axis driving naïve CD4+ T cell activation and differentiation into Th17 cells.

scholarly journals IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Hsing-Chuan Tsai ◽  
Sharlene Velichko ◽  
Li-Yin Hung ◽  
Reen Wu
Keyword(s):  
Cell Differentiation ◽  
Host Defense ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Critical Role ◽  
Klebsiella Pneumonia ◽  
Antimicrobial Proteins ◽  
Cytokines And Chemokines ◽  
Th17 Cell Differentiation

The significance of Th17 cells and interleukin- (IL-)17A signaling in host defense and disease development has been demonstrated in various infection and autoimmune models. Numerous studies have indicated that Th17 cells and its signature cytokine IL-17A are critical to the airway’s immune response against various bacteria and fungal infection. Cytokines such as IL-23, which are involved in Th17 differentiation, play a critical role in controllingKlebsiella pneumonia(K. pneumonia) infection. IL-17A acts on nonimmune cells in infected tissues to strengthen innate immunity by inducing the expression of antimicrobial proteins, cytokines, and chemokines. Mice deficient in IL-17 receptor (IL-17R) expression are susceptible to infection by various pathogens. In this review, we summarize the recent advances in unraveling the mechanism behind Th17 cell differentiation, IL-17A/IL-17R signaling, and also the importance of IL-17A in pulmonary infection.

scholarly journals Identification of Novel Molecular Markers of Human Th17 Cells

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1611 ◽  
Author(s):  
Anna Sałkowska ◽  
Kaja Karaś ◽  
Iwona Karwaciak ◽  
Aurelia Walczak-Drzewiecka ◽  
Mariusz Krawczyk ◽  
...  
Keyword(s):  
Host Defense ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cathepsin L ◽  
Cell Type ◽  
Protein Levels ◽  
Pathological Conditions ◽  
Th17 Lymphocytes ◽  
New Information ◽  
Apolipoprotein D

Th17 cells are important players in host defense against pathogens such as Staphylococcus aureus, Candida albicans, and Bacillus anthracis. Th17 cell-mediated inflammation, under certain conditions in which balance in the immune system is disrupted, is the underlying pathogenic mechanism of certain autoimmune disorders, e.g., rheumatoid arthritis, Graves’ disease, multiple sclerosis, and psoriasis. In the present study, using transcriptomic profiling, we selected genes and analyzed the expression of these genes to find potential novel markers of Th17 lymphocytes. We found that APOD (apolipoprotein D); C1QL1 (complement component 1, Q subcomponent-like protein 1); and CTSL (cathepsin L) are expressed at significantly higher mRNA and protein levels in Th17 cells than in the Th1, Th2, and Treg subtypes. Interestingly, these genes and the proteins they encode are well associated with the function of Th17 cells, as these cells produce inflammation, which is linked with atherosclerosis and angiogenesis. Furthermore, we found that high expression of these genes in Th17 cells is associated with the acetylation of H2BK12 within their promoters. Thus, our results provide new information regarding this cell type. Based on these results, we also hope to better identify pathological conditions of clinical significance caused by Th17 cells.

scholarly journals IL-1 Receptor Blockade Alleviates Graft-versus-Host Disease through Downregulation of an Interleukin-1β-Dependent Glycolytic Pathway in Th17 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Min-Jung Park ◽  
Seung Hoon Lee ◽  
Sung-Hee Lee ◽  
Eun-Jung Lee ◽  
Eun-Kyung Kim ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
T Cell Response ◽  
Host Disease ◽  
Graft Versus Host ◽  
Th17 Cell Differentiation

T helper (Th) 17 cells are a subset of Th cells expressing interleukin- (IL-) 17 and initiating an inflammatory response in autoimmune diseases. Graft-versus-host disease (GVHD) is an immune inflammatory disease caused by interactions between the adaptive immunity of donor and recipient. The Th17 lineage exhibits proinflammatory activity and is believed to be a central player in GVHD. IL-1 performs a key function in immune responses and induces development of Th17 cells. Here, we show that blockade of IL-1 signaling suppresses Th17 cell differentiation and alleviates GVHD severity. We hypothesized that the IL-1 receptor antagonist (IL-1Ra) would suppress Th17 cell differentiationin vitrovia inhibition of glycolysis-related genes. Blockade of IL-1 using IL-1Ra downregulated Th17 cell differentiation, an alloreactive T cell response, and expression of genes of the glycolysis pathway. Severity of GVHD was reduced in mice with a transplant of IL-Ra-treated cells, in comparison with control mice. To clarify the mechanisms via which IL-1Ra exerts the therapeutic effect, we demonstratedin vivothat IL-1Ra decreased the proportion of Th17 cells, increased the proportion of FoxP3-expressing T regulatory (Treg) cells, and inhibited expression of glycolysis-related genes and suppressed Th17 cell development and B-cell activation. These results suggest that blockade of IL-1 signaling ameliorates GVHD via suppression of excessive T cell-related inflammation.

scholarly journals T cell derived HB-EGF prevents Th17 cell differentiation in an autocrine way

2021 ◽  
Author(s):  
Felicity Macdonald ◽  
Jorg van Loosdregt ◽  
Dietmar M W Zaiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Autoimmune Diseases ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
T Helper 17

ABSTRACTCD4 T cells critically contribute to host immunity against infections, but can also contribute to the development of autoimmune diseases. The underlying mechanisms that govern differentiation of naïve CD4 T cells into different effector populations remain poorly understood. Here, we show that the expression of the Epidermal Growth Factor (EGF)-like growth factor HB-EGF by CD4 T cells sustained their expression of Interleukin (IL)-2 and reduced their capacity to differentiate into T Helper 17 (Th17) cells. Concordantly, mice with a T cell specific deficiency of HB-EGF showed an enhanced differentiation of naïve CD4 T cells into Th17 cells and a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Furthermore, transfer of naïve HB-EGF-deficient CD4 T cells into Rag1-/- mice led to the rapid induction of multi-organ inflammation in recipient mice. Together, our data reveal a novel mechanism by which an HB-EGF-mediated constrain on Th17 differentiation prevents the development of autoimmune diseases.SUMMARYCD4 T cell activation induces the expression of the EGFR and its high-affinity ligand HB-EGF. HB-EGF sustains IL-2 expression in an autocrine manner, preventing the differentiation of Th17 cells and the subsequent induction of Th17 cell-mediated autoimmune diseases.

Evidence for Associations Between Th1/Th17 “Hybrid” Phenotype and Altered Lipometabolism in Very Severe Graves Orbitopathy

2020 ◽  
Vol 105 (6) ◽  
pp. 1851-1867 ◽  
Author(s):  
Sijie Fang ◽  
Shuo Zhang ◽  
Yazhuo Huang ◽  
Yu Wu ◽  
Yi Lu ◽  
...  
Keyword(s):  
T Cell ◽  
Th17 Cell ◽  
Th17 Cells ◽  
T Cell Subsets ◽  
Th1 Cell ◽  
Effector T Cell ◽  
Cell Lineages ◽  
Graves Orbitopathy ◽  
Ifn Γ

Abstract Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.

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