Exopolysaccharide Produced by Lactobacillus casei Promotes the Differentiation of CD4+ T Cells into Th17 Cells in BALB/c Mouse Peyer’s Patches in Vivo and in Vitro

2020 ◽  
Vol 68 (9) ◽  
pp. 2664-2672 ◽  
Author(s):  
Qiqi Ren ◽  
YanJun Tang ◽  
Lili Zhang ◽  
Yan Xu ◽  
Ning Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Lactobacillus Casei ◽  
Peyer's Patches ◽  
Peyer’S Patches

IL-17A-Expressing CD4+ T Cells Must Acquire the Expression of T-Bet and IFN-γto Destroy Tumor Cells In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 468-468
Author(s):  
Pawel Muranski ◽  
Sid P Kerkar ◽  
Zachary A Borman ◽  
Robert Reger ◽  
Luis Sanchez-Perez ◽  
...  
Keyword(s):  
T Cells ◽  
Treatment Efficacy ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
End Effector ◽  
Polarized Cells ◽  
Ifn Γ

Abstract Abstract 468 We have recently demonstrated that Th17-polarized TCR transgenic CD4+ T cells specific for TRP-1 melanoma antigen are superior to Th1-polarized cells in mediating effective anti-tumor responses against advanced disease after adoptive transfer. The therapeutic activity of Th17-skewed cells is critically dependent on their ability to secrete IFN-γ, suggesting that the Th17 subset might evolve in vivo. However, the developmental program of Th17-polarized cells in vivo remains substantially un- elucidated. We developed a novel TCR-transduction technique that enabled us to rapidly confer specificity for a cognate antigen upon any population of T cells, regardless of its genetic background, its previous polarization history or its state of differentiation. Using adoptive transfers into tumor-bearing hosts, we were able to study the functionality of these genetically-engineered T cells in vivo. In vitro, CD4+ T cells cultured in type 17 conditions acquired end-effector phenotype (CD62Llow, CD45RBlow), but proliferated slower than cells grown in type 1 condition. Thus, we hypothesized that Th17-polarized cells might represent a less mature, more central-memory like subset. This notion was supported by their ability to secrete high quantities of IL-2 and higher expression of IL-7 receptor. In contrast, Th1-polarized cells upon in vitro re-stimulation upregulated PRDM1 that encodes BLIMP1, a molecule associated with the end-effector senescent phenotype. Moreover, Th1-skewed cells overexpressed caspase 3 and were prone to activation-induced cell death as measured by annexin V assay, while type 17 cells were resistant to apoptosis, and robustly expanded in secondary cultures. Using the TCR gene transfer technique we tested the treatment outcomes when Th17-polarized cells deficient for IL-17A were used. In contrast to wild-type (WT)-derived Th17 cells that effectively eradicated established tumors, we observed significant impairment of treatment with IL-17A-deficent cells. Similarly, we observed reduction in treatment efficacy when CCR6-deficient Th17 cells were transferred. CCR6 is a receptor for CCL20, a chemokine highly induced Th17 cells and thought to contribute to the trafficking of those cells to the site of inflammation. In both cases however, the addition of exogenous vaccination and IL-2 significantly improved treatment efficacy. Thus, we concluded that Th17-associated factors play the role in the anti-cancer activity of type 17 cells. To address the question whether plasticity of Th17-skewed effectors is important for their function upon ACT, we treated animals with TCR-transduced Th17-skewed cells derived from IFN-γ-deficient CD4+ cells as well as from t-bet-deficient mice, which are not able to develop type 1 responses. In contrast to WT-derived Th17 effectors, IFN-γ-deficient cells did not show any anti-tumor activity, while t-bet-deficient Th17 cells were able to mediate only minimal delay in tumor growth, suggesting that indeed the capacity to acquire Th1-like properties is essential for the anti-tumor function of Th17-skewed lymphocytes. Overall, here we demonstrate that TCR gene engineered Th17-polarized cells can efficiently treat advanced tumor. The high activity of in vitro-generated anti-tumor Th17 cells relies on the contribution of type 17-associated characteristics, including both the secretion of inflammatory factors IL-17A and CCL20, as well as the superior capacity to survive and expand upon the secondary stimulation. Importantly however, type 1-defining t-bet-mediated plasticity in the lineage commitment is required for the full therapeutic effect, underscoring the dualistic nature of Th17-skewed cells. Disclosures: No relevant conflicts of interest to declare.

Hyperactivable NFAT1 Ameliorates Autoimmune Encephalitis In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 711-711
Author(s):  
Srimoyee Ghosh ◽  
Sergei B Koralov ◽  
Irena Stevanovic ◽  
Mark S Sundrud ◽  
Yoshiteru Sasaki ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Autoimmune Encephalitis ◽  
Cell Types ◽  
Wild Type ◽  
Ifn Γ

Abstract Abstract 711 Naïve CD4 T cells differentiate into diverse effector and regulatory subsets to coordinate the adaptive immune response. TH1 and TH2 effector subsets produce IFN-γ and IL-4, respectively, whereas proinflammatory TH17 cells are key regulators of autoimmune inflammation, characteristically produce IL-17 and IL-22 and differentiate in the presence of inflammatory cytokines like IL-6 and IL-21 together with TGF-β. Naive T cells can also differentiate into tissue-protective induced T regulatory (iTreg) cells. NFAT proteins are highly phosphorylated and reside in the cytoplasm of resting cells. Upon dephosphorylation by the Ca2+/calmodulin-dependent serine phosphatase calcineurin, NFAT proteins translocate to the nucleus, where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the role of the Ca/NFAT signaling pathway in regulating T cell differentiation and the development of autoimmune diseases. We generated transgenic mice conditionally expressing a hyperactivable version of NFAT1 (AV-NFAT1) from the ROSA26 locus. To restrict AV-NFAT1 expression to the T cell compartment, ROSA26-AV-NFAT1 transgenic mice were bred to CD4-Cre transgenic mice. Naïve CD4 T cells freshly isolated from AV mice produced significantly less IL-2 but increased amounts of the inhibitory cytokine IL-10. To investigate the role of NFAT1 in the generation of TH1, TH2, Tregand TH17 cells, the respective cell types were generated from CD4 T cells of AV mice by in vitro differentiation. T cells from AV-NFAT1 mice exhibited a dysregulation of cytokine expression, producing more IFN-γ and less IL-4. While the numbers of CD4+CD25+ “natural” Treg cells in peripheral lymphoid organs and their in vitro suppressive functions were slightly decreased in AV mice, iTreg generation from CD4+CD25- T cells of AV mice as compared to wild type cells was markedly enhanced. Moreover, TH17 cells generated in vitro from CD4 T cells of AV mice in the presence of IL-6, IL-21 and TGF-β exhibited dramatically increased expression of both IL-10 and IL-17 as compared to wild type controls. To investigate putative NFAT binding sites in the IL-10 and IL-17 gene loci, we performed chromatin immunoprecipitation experiments. We show that NFAT1 can bind at the IL-17 locus at 3 out of 9 CNS regions which are accessible specifically during TH17 but not during TH1 and TH2 differentiation. Furthermore, we provide evidence that NFAT1 binds one CNS region in the IL10-locus in TH17 cells. To verify our observations in vivo, we induced experimental autoimmune encephalitis (EAE) in AV mice and wild type controls with the immunodominant myelin antigen MOG33-55 emulsified in complete Freund‘s adjuvant. While wild type animals showed a normal course of disease with development of tail and hind limb paralysis after approximately 10 days, AV mice showed a markedly weaker disease phenotype with less severe degrees of paralysis and accelerated kinetics of remission. Moreover at the peak of the response, there were fewer CD4+CD25- but more CD4+CD25+ T cells in the CNS of AV animals compared to wild type controls. Surprisingly, these cells produced significantly more IL-2, IL-17 and IFN-γ upon restimulation, even though they displayed decreased disease. In summary, our data provide strong evidence that NFAT1 contributes to the regulation of IL-10 and IL-17 expression in TH17 cells and show that increasing NFAT1 activity can ameliorate autoimmune encephalitis. This could occur in part through upregulation of IL-10 expression as observed in vitro, but is also likely to reflect increased infiltration of regulatory T cells into the CNS as well as increased conversion of conventional T cells into Foxp3+ regulatory T cells within the CNS. Disclosures: No relevant conflicts of interest to declare.

Critical and Opposing Effects of T Cell-Derived TNFα and Interferon-γ on IL-17 Induction Assessed in Vitro and in Vivo Following Allogeneic Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3482-3482
Author(s):  
Minghui Li ◽  
Kai Sun ◽  
Mark Hubbard ◽  
Doug Redelman ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Allogeneic Bmt

Abstract IL-17-producing CD4 T cells (Th17) are a recently identified T helper subset that plays a role in mediating host defense to extracellular bacteria infections and is involved in the pathogenesis of many autoimmune diseases. In vitro induction of IL-17 in murine CD4+ T cells has been shown to be dependent on the presence of the proinflammatory cytokines TGF-β and IL-6 whereas IFNγ can suppress the development of Th17 cells. In the current study, we examined the roles of TNFα and IFNγ on IL-17 production by purified T cells in vitro and in vivo after allogeneic bone marrow transplantation (BMT). We present findings that expression of TNFα by the T cell itself is necessary for optimal development of Th17 under in vitro polarizing conditions. A novel role for T cell-derived TNFα in Th17 induction was observed when in vitro polarization of Tnf−/−CD4+ T cells resulted in marked reductions in IL-17+CD4+ T cells compared to Tnf+/+CD4+ T cells. In marked contrast, T cell-derived IFNγ markedly inhibited Th17 development as more IL-17+CD4+ T cells were found in Ifnγ−/−CD4+ T cells than in Ifnγ+/+CD4+ T cells, and of particular interest was the dramatic increase in IL-17+CD8+ cells from Ifnγ−/− mice. To determine if T cell-derived TNFα or IFNγ can regulate Th17 development in vivo we examined the differentiation of alloreactive donor T cells following allogeneic BMT. We have found that donor-derived Th17 cells can be found in lymphoid tissues and GVHD-affected organs after allogeneic BMT. However, transfer of Tnf−/− CD4+ T cells after allogeneic BMT resulted in marked reductions in Th17 cells in the spleen (18×103 vs 7×103, P<0.05). In agreement with the in vitro data and in contrast to what was observed with transfer of Tnf−/− CD4+ T cells, transfer of donor Ifnγ−/− T cells resulted in marked increases in not only IL-17+CD4+ but also IL-17+CD8+ T cells infiltrating the liver (7×103 vs 14×103, P<0.05; 4×104 vs 12.5×104, P<0.05). These results suggest that the donor T cell-derived TNFα and IFNγ opposingly regulate IL-17 induction of both CD4+ and CD8+ T cells in vitro and after allogeneic BMT which correlates with GVHD pathology.

scholarly journals In vitro alteration of receptors for vasoactive intestinal peptide changes the in vivo localization of mouse T cells.

1984 ◽  
Vol 160 (4) ◽  
pp. 1054-1069 ◽  
Author(s):  
C A Ottaway
Keyword(s):  
T Cells ◽  
Vasoactive Intestinal Peptide ◽  
Receptor Expression ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Mesenteric Lymph Nodes ◽  
Dose Dependent Decrease ◽  
Dose Dependent

The capacity of T lymphocytes exposed in vitro to the neuropeptide vasoactive intestinal peptide (VIP) to bind VIP in vitro and to migrate to different tissues in vivo has been studied. VIP treatment of T cells resulted in a time- and dose-dependent loss of the ability of T cells to specifically bind radioiodinated VIP. Altered binding was due to a decrease in the expression of cellular receptors for VIP on the treated cells rather than an alteration in the affinity of the cells for the neuropeptide. Alteration of VIP receptor expression was not associated with a change in the expression of Thy-1, Lyt-1, or Lyt-2 surface markers by the treated cells. VIP treatment of T cells in vitro resulted, however, in a dose-dependent decrease in the ability of the treated cells to localize in mesenteric lymph nodes (MLN) and Peyer's patches of recipient animals at early times after cell transfer, and this was due to a selective decrease in the rate of accumulation of the treated cells in these tissues. There was no alteration in the distribution of VIP-treated cells in the blood, spleen, liver, or other major organs of the recipient animals. It is concluded that the presence of VIP receptors on T cells facilitates the entry of T cells into MLN and Peyer's patches in vivo, and it is proposed that this effect is mediated by T cell-VIP interactions in the vicinity of the specialized endothelium of those tissues.

scholarly journals Transcriptome profiling of pathogen-specific CD4 T cells identifies T-cell-intrinsic caspase-1 as an important regulator of Th17 differentiation

2018 ◽  
Author(s):  
Yajing Gao ◽  
Krystin Deason ◽  
Aakanksha Jain ◽  
Ricardo A Irizarry-Caro ◽  
Igor Dozmorov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Transcriptome Profiling ◽  
Caspase 1 ◽  
Th17 Differentiation ◽  
Cell Transcriptome

One sentence summaryOur study revealed that DCs shape distinct pathogen-specific CD4 T cell transcriptome and from which, we discovered an unexpected role for T-cell-intrinsic caspase-1 in promoting Th17 differentiation.ABSTRACTDendritic cells (DCs) are critical for priming and differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells leading to effector heterogeneity remains elusive. Here we have used an in vitro approach to prime naïve CD4 T cells by DCs stimulated with distinct pathogens. We have found that such pathogen-primed CD4 T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. In contrast to cytokine-polarized Th17 cells that display signatures of terminal differentiation, pathogen-primed Th17 cells maintain a high degree of heterogeneity and plasticity. Further analysis identified caspase-1 as one of the genes upregulated only in pathogen-primed Th17 cells but not in cytokine-polarized Th17 cells. T-cell-intrinsic caspase-1, independent of its function in inflammasome, is critical for inducing optimal pathogen-driven Th17 responses. More importantly, T cells lacking caspase-1 fail to induce colitis following transfer into RAG-deficient mice, further demonstrating the importance of caspase-1 for the development of pathogenic Th17 cells in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation.

scholarly journals Transcriptional profiling identifies caspase-1 as a T cell–intrinsic regulator of Th17 differentiation

2020 ◽  
Vol 217 (4) ◽  
Author(s):  
Yajing Gao ◽  
Krystin Deason ◽  
Aakanksha Jain ◽  
Ricardo A. Irizarry-Caro ◽  
Igor Dozmorov ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Transcriptional Profiling ◽  
Critical Role ◽  
Caspase 1

Dendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with specific pathogens to prime CD4 T cells in vitro and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More specifically, the transcriptome of in vitro C. rodentium–primed Th17 cells resembled that of Th17 cells primed following infection in vivo but was remarkably distinct from cytokine-polarized Th17 cells. We identified caspase-1 as a unique gene up-regulated only in pathogen-primed Th17 cells and discovered a critical role for T cell–intrinsic caspase-1, independent of inflammasome, in optimal priming of Th17 responses. T cells lacking caspase-1 failed to induce colitis or confer protection against C. rodentium infection due to suboptimal Th17 cell differentiation in vivo. This study underlines the importance of DC-mediated priming in identifying novel regulators of T cell differentiation.

Comparison of In Vitro and In Vivo Effects of Infliximab on Cytokine Production in Proliferating CD4+ T Cells in Patients with Rheumatoid Arthritis

2015 ◽  
Vol 1 (2) ◽  
pp. 122-128
Author(s):  
Syuichi Koarada ◽  
Yuri Sadanaga ◽  
Natsumi Nagao ◽  
Satoko Tashiro ◽  
Rie Suematsu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production

scholarly journals Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes

2000 ◽  
Vol 191 (3) ◽  
pp. 541-550 ◽  
Author(s):  
Zhengbin Lu ◽  
Lingxian Yuan ◽  
Xianzheng Zhou ◽  
Eduardo Sotomayor ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cell Communication ◽  
Cd8 T Cell ◽  
Cd4 Help ◽  
T Cell Help

In many cases, induction of CD8+ CTL responses requires CD4+ T cell help. Recently, it has been shown that a dominant pathway of CD4+ help is via antigen-presenting cell (APC) activation through engagement of CD40 by CD40 ligand on CD4+ T cells. To further study this three cell interaction, we established an in vitro system using dendritic cells (DCs) as APCs and influenza hemagglutinin (HA) class I and II peptide–specific T cell antigen receptor transgenic T cells as cytotoxic T lymphocyte precursors and CD4+ T helper cells, respectively. We found that CD4+ T cells can provide potent help for DCs to activate CD8+ T cells when antigen is provided in the form of either cell lysate, recombinant protein, or synthetic peptides. Surprisingly, this help is completely independent of CD40. Moreover, CD40-independent CD4+ help can be documented in vivo. Finally, we show that CD40-independent T cell help is delivered through both sensitization of DCs and direct CD4+–CD8+ T cell communication via lymphokines. Therefore, we conclude that CD4+ help comprises at least three components: CD40-dependent DC sensitization, CD40-independent DC sensitization, and direct lymphokine-dependent CD4+–CD8+ T cell communication.

scholarly journals Human Effector Memory CD4+ T Cells Directly Recognize Allogeneic Endothelial Cells In Vitro and In Vivo

2007 ◽  
Vol 179 (7) ◽  
pp. 4397-4404 ◽  
Author(s):  
Stephen L. Shiao ◽  
Nancy C. Kirkiles-Smith ◽  
Benjamin R. Shepherd ◽  
Jennifer M. McNiff ◽  
Edward J. Carr ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Memory Cd4 T Cells

scholarly journals Peyer's Patch Dendritic Cells Process Viral Antigen from Apoptotic Epithelial Cells in the Intestine of Reovirus-infected Mice

2004 ◽  
Vol 200 (2) ◽  
pp. 235-245 ◽  
Author(s):  
Marina N. Fleeton ◽  
Nikhat Contractor ◽  
Francisco Leon ◽  
J. Denise Wetzel ◽  
Terence S. Dermody ◽  
...  
Keyword(s):  
T Cells ◽  
Epithelial Cells ◽  
Cd4 T Cells ◽  
Cell Protein ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Antigen Uptake ◽  
Cross Presentation

We explored the role of Peyer's patch (PP) dendritic cell (DC) populations in the induction of immune responses to reovirus strain type 1 Lang (T1L). Immunofluorescence staining revealed the presence of T1L structural (σ1) and nonstructural (σNS) proteins in PPs of T1L-infected mice. Cells in the follicle-associated epithelium contained both σ1 and σNS, indicating productive viral replication. In contrast, σ1, but not σNS, was detected in the subepithelial dome (SED) in association with CD11c+/CD8α−/CD11blo DCs, suggesting antigen uptake by these DCs in the absence of infection. Consistent with this possibility, PP DCs purified from infected mice contained σ1, but not σNS, and PP DCs from uninfected mice could not be productively infected in vitro. Furthermore, σ1 protein in the SED was associated with fragmented DNA by terminal deoxy-UTP nick-end labeling staining, activated caspase-3, and the epithelial cell protein cytokeratin, suggesting that DCs capture T1L antigen from infected apoptotic epithelial cells. Finally, PP DCs from infected mice activated T1L-primed CD4+ T cells in vitro. These studies show that CD8α−/CD11blo DCs in the PP SED process T1L antigen from infected apoptotic epithelial cells for presentation to CD4+ T cells, and therefore demonstrate the cross-presentation of virally infected cells by DCs in vivo during a natural viral infection.

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