Probiotic modulation of dendritic cells and T cell responses in the intestine

Over the past decade it has become clear that probiotic and commensal interactions with mucosal dendritic cells in the lamina propria or epithelial cells lining the mucosa can modulate specific functions of the mucosal immune system. Innate pattern-recognition receptors such as TLRs, NLRs and CLRs play a crucial role in the host recognition of probiotics and other microorganism. Signalling via these receptors directly influences the chemokine and cytokine response of dendritic cells as well as the crosstalk between the epithelium and the immune cells in the lamina propria. This can influence the population of effector and regulatory T cell subsets in the mucosa. Immune assays with probiotics have shown that the in vitro immune response is both species and strain-specific. Such assays may be useful for the selection of probiotic strains that have beneficial effects on the regulation of intestinal inflammation but more comparative studies are needed to confirm recent findings. A better understanding of the molecular mechanisms of probiotics, the effect of dose, and frequency of administration on microbial sampling by mucosal APC will also help to clarify the value of immune assays as selection criteria for probiotics.

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Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Blood ◽

10.1182/blood-2004-03-1059 ◽

2005 ◽

Vol 105 (2) ◽

pp. 697-702 ◽

Cited By ~ 65

Author(s):

Sonia Feau ◽

Valeria Facchinetti ◽

Francesca Granucci ◽

Stefania Citterio ◽

David Jarrossay ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Molecular Mechanisms ◽

Interleukin 2 ◽

Adaptive Immune ◽

Deficient Mice ◽

Mouse System

Abstract Dendritic cells (DCs) are involved in the initiation and regulation of innate and adaptive immune responses. Several molecular mechanisms regulate these diverse DC functions, and we have previously reported that mouse dendritic cells (mDCs) can produce interleukin-2 (IL-2) in vitro and in vivo, in response to microbial activation and T-cell-mediated stimuli. This property is shared by different DC subtypes, including Langerhans cells. Here we show that, on appropriate stimulation, human DCs, both plasmacytoid and myeloid subtypes, also express IL-2. Interestingly, the production of IL-2 by myeloid DCs is induced by T-cell-mediated stimuli and depends on the presence of IL-15. The key role of this cytokine in regulating IL-2 production was also confirmed in the mouse system. In particular, we could show that DCs from IL-15-deficient mice were strongly impaired in the ability to produce IL-2 after interactions with different microbial stimuli. Our results indicate that DC-produced IL-2 is tightly coregulated with the expression of IL-15.

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Interaction of Type 1 Porcine Reproductive and Respiratory Syndrome Virus With In Vitro Derived Conventional Dendritic Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.674185 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yanli Li ◽

Enric Mateu

Keyword(s):

Dendritic Cells ◽

T Cell ◽

T Cell Subsets ◽

Poly I:C ◽

Respiratory Syndrome Virus ◽

Mhc I ◽

Live Virus ◽

The Impact ◽

Tlr7 Ligand

The present study delineates the interaction of a typical PRRSV1.1 isolate 3267 (moderate virulence) with in vitro derived pig conventional dendritic cells, cDC1, cDC2, and a CD14+ population (designated as CD14+ DCs). cDC1 and cDC2 were not susceptible to 3267 infection, but a fraction of CD14+ DCs were infected. After exposure to the virus, all three DC types remained immature as determined by no increase of maturation molecules (MHC-I, MHC-II, CD80/86, CCR7), no release of cytokines, no modification of antigen presentation abilities, and no alteration of endocytic/phagocytic capabilities. However, when infected MARC-145 cells were used as a source of viral antigens, cDC2 and CD14+ DCs showed a significant increase in the expression of maturation molecules and substantial release of cytokines, notably IL-12/IL-23p40 (by both DC types) and IL-10 (by CD14+ DCs). To address the impact of PRRSV1 3267 on TLR3- and TLR7-mediated activation, cDC1, cDC2, and CD14+ DCs were inoculated by the virus (live or UV-inactivated) for 6 h prior to or simultaneously with the addition of poly I:C (TLR3 ligand) or gardiquimod (TLR7 ligand; not used for cDC1). Compared with using TLR ligand alone, combination with the virus did not result in any alteration to the maturation markers on all DC types but changed the cytokine response to either TLR3 or TLR7 ligand. Pre-exposure of cDC2 or CD14+ DCs to the live virus resulted in an increased production of IFN-α upon poly I:C stimulation, while pre-exposure to UV-inactivated virus tended to enhance the release of IL-10 upon gardiquimod stimulation. Simultaneous addition of the live virus and the TLR ligand either had no effect (mainly in cDC2) or impaired most of the cytokine release after gardiquimod stimulation (in CD14+ DCs). When used as antigen presenting cells, cDC2 pre-inoculated by the live virus before addition of gardiquimod impaired the proliferation of CD4–CD8– T cells. In the case of CD14+ DCs, pre-exposure to the live virus or simultaneously added with TLR3 or TLR7 ligand largely decreased the proliferation of CD4–CD8+ and CD4–CD8+ T-cell subsets. For cDC1, no significant changes were observed in cytokine responses or T-cell proliferation after poly I:C stimulation. Of note, cDC1 had a short life during in vitro culturing, for which the results obtained might be biased. Overall, exposure to PRRSV1 did not induce maturation of cDC1, cDC2, or CD14+ DCs, but modified TLR3 and TLR7-associated responses (except for cDC1), which may affect the development of adaptive immunity during PRRSV1 infection. Moreover, the sensing of infected cells was different from that of the free virus.

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Allergen-induced resistin-like molecule-α promotes esophageal epithelial cell hyperplasia in eosinophilic esophagitis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00141.2014 ◽

2014 ◽

Vol 307 (5) ◽

pp. G499-G507 ◽

Cited By ~ 6

Author(s):

Parm Mavi ◽

Rituraj Niranjan ◽

Parmesh Dutt ◽

Asifa Zaidi ◽

Jai Shankar Shukla ◽

...

Keyword(s):

Insulin Resistance ◽

T Cell ◽

Epithelial Cell ◽

Layer Thickness ◽

Eosinophilic Esophagitis ◽

Intestinal Inflammation ◽

Basal Layer ◽

T Cell Subsets ◽

Cell Hyperplasia

Resistin-like molecule (Relm)-α is a secreted, cysteine-rich protein belonging to a newly defined family of proteins, including resistin, Relm-β, and Relm-γ. Although resistin was initially defined based on its insulin-resistance activity, the family members are highly induced in various inflammatory states. Earlier studies implicated Relm-α in insulin resistance, asthmatic responses, and intestinal inflammation; however, its function still remains an enigma. We now report that Relm-α is strongly induced in the esophagus in an allergen-challenged murine model of eosinophilic esophagitis (EoE). Furthermore, to understand the in vivo role of Relm-α, we generated Relm-α gene-inducible bitransgenic mice by using lung-specific CC-10 promoter (CC10-rtTA- Relm-α). We found Relm-α protein is significantly induced in the esophagus of CC10-rtTA- Relm-α bitransgenic mice exposed to doxycycline food. The most prominent effect observed by the induction of Relm-α is epithelial cell hyperplasia, basal layer thickness, accumulation of activated CD4+ and CD4− T cell subsets, and eosinophilic inflammation in the esophagus. The in vitro experiments further confirm that Relm-α promotes primary epithelial cell proliferation but has no chemotactic activity for eosinophils. Taken together, our studies report for the first time that Relm-α induction in the esophagus has a major role in promoting epithelial cell hyperplasia and basal layer thickness, and the accumulation of activated CD4+ and CD4− T cell subsets may be responsible for partial esophageal eosinophilia in the mouse models of EoE. Notably, the epithelial cell hyperplasia and basal layer thickness are the characteristic features commonly observed in human EoE.

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Transcription factor GATA-1 potently represses the expression of the HIV-1 coreceptor CCR5 in human T cells and dendritic cells

Blood ◽

10.1182/blood-2005-03-0857 ◽

2005 ◽

Vol 106 (10) ◽

pp. 3440-3448 ◽

Cited By ~ 14

Author(s):

Mark S. Sundrud ◽

Scott E. VanCompernolle ◽

Karla A. Eger ◽

Tullia C. Bruno ◽

Arun Subramaniam ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Chemokine Receptor ◽

Molecular Mechanisms ◽

T Cell Subsets ◽

Critical Determinant ◽

Human T Cell ◽

Human T Cells ◽

Hiv 1

AbstractCC chemokine receptor 5 (CCR5) is the major HIV-1 coreceptor and its expression levels are a critical determinant of HIV-1 infection. However, the molecular mechanisms of CCR5 regulation in primary targets of HIV-1 remain unknown. Despite binding to conserved DNA elements, we show that the transcription factors GATA binding protein 1 (GATA-1) and GATA-3 differentially suppress the expression of CCR5 in stem-cell–derived dendritic cells and primary human T-cell subsets. In addition, GATA-1 expression was also more potent than GATA-3 in suppressing T helper 1 (Th1)–associated genes, interferon-γ (IFNγ), and CXC chemokine receptor-3 (CXCR3). GATA-1, but not GATA-3, potently suppressed CCR5 transcription, thereby rendering human T cells resistant to CCR5-tropic HIV-1 infection. However, GATA-1 could also serve as a surrogate for GATA-3 in its canonic role of programming Th2 gene expression. These findings provide insight into GATA-3–mediated gene regulation during T-cell differentiation. Importantly, decoding the mechanisms of GATA-1–mediated repression of CCR5 may offer an opportunity to develop novel approaches to inhibit CCR5 expression in T cells.

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B Lymphocytes, but Not Dendritic Cells, Efficiently HIV-1 Trans Infect Naive CD4+ T Cells: Implications for the Viral Reservoir

mBio ◽

10.1128/mbio.02998-20 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Abigail Gerberick ◽

Diana C. DeLucia ◽

Paolo Piazza ◽

Mounia Alaoui-El-Azher ◽

Charles R. Rinaldo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

B Lymphocytes ◽

T Cell Subsets ◽

Viral Reservoir ◽

Myeloid Dendritic Cells ◽

And Control ◽

Hiv 1

ABSTRACT Insight into the establishment and maintenance of HIV-1 infection in resting CD4+ T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+ naive T cells (TN) than in the memory T cell subsets, recent studies have shown that TN harbor a large pool of replication-competent virus. Interestingly, however, TN are highly resistant to direct (cis) HIV-1 infection in vitro, in particular to R5-tropic HIV-1, as TN do not express CCR5. In this study, we investigated whether TN could be efficiently HIV-1 trans infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficiently trans infect TN in vitro. In contrast, both B cells and DC mediated HIV-1 trans infection of memory and activated CD4+ T cells. Moreover, we found that TN isolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA than TN isolated from progressors. This is consistent with our previous finding that antigen-presenting cells (APC) derived from NP do not efficiently trans infect CD4+ T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediated trans infection of TN with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. IMPORTANCE The latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy (ART) represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication-competent HIV-1 has been isolated from TN, and CCR5-tropic HIV-1 has been recovered from CCR5neg TN from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5neg TN are efficiently trans infected with R5-tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TN isolated from NP harbor no or significantly fewer copies of HIV-1 DNA than those from ART-suppressed progressors. These findings support that B cell-mediated trans infection of TN with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.

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Differential Effects of Control and Antigen-Specific T Cells on Intracellular Mycobacterial Growth

Infection and Immunity ◽

10.1128/iai.71.4.1763-1773.2003 ◽

2003 ◽

Vol 71 (4) ◽

pp. 1763-1773 ◽

Cited By ~ 51

Author(s):

S. Worku ◽

D. F. Hoft

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor ◽

Mrna Expression ◽

Molecular Mechanisms ◽

Fas Ligand ◽

T Cell Subsets ◽

Intracellular Growth ◽

Mycobacterial Antigens

ABSTRACT We investigated the effects of peripheral blood mononuclear cells expanded with irrelevant control and mycobacterial antigens on the intracellular growth of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in human macrophages. More than 90% of the cells present after 1 week of in vitro expansion were CD3+. T cells were expanded from purified protein derivative-negative controls, persons with latent tuberculosis, and BCG-vaccinated individuals. T cells expanded with nonmycobacterial antigens enhanced the intracellular growth of BCG in suboptimal cultures of macrophages. T cells expanded with live BCG or lysates of Mycobacterium tuberculosis directly inhibited intracellular BCG. Recent intradermal BCG vaccination significantly enhanced the inhibitory activity of T cells expanded with mycobacterial antigens (P < 0.02), consistent with the induction of memory-immune inhibitory T-cell responses. Selected mycobacterial antigens (Mtb41 > lipoarabinomannan > 38kd > Ag85B > Mtb39) expanded inhibitory T cells, demonstrating the involvement of antigen-specific T cells in intracellular BCG inhibition. We studied the T-cell subsets and molecular mechanisms involved in the memory-immune inhibition of intracellular BCG. Mycobacteria-specific γδ T cells were the most potent inhibitors of intracellular BCG growth. Direct contact between T cells and macrophages was necessary for the BCG growth-enhancing and inhibitory activities mediated by control and mycobacteria-specific T cells, respectively. Increases in tumor necrosis factor alpha, interleukin-6, transforming growth factor β, and vascular endothelial growth factor mRNA expression were associated with the enhancement of intracellular BCG growth. Increases in gamma interferon, FAS, FAS ligand, perforin, granzyme, and granulysin mRNA expression were associated with intracellular BCG inhibition. These culture systems provide in vitro models for studying the opposing T-cell mechanisms involved in mycobacterial survival and protective host immunity.

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B LYMPHOCYTES, BUT NOT DENDRITIC CELLS, EFFICIENTLY HIV-1 TRANS-INFECT NAÏVE CD4+ T CELLS: IMPLICATIONS FOR THE VIRAL RESERVOIR

10.1101/2020.10.22.351627 ◽

2020 ◽

Author(s):

Abigail Gerberick ◽

Diana C. DeLucia ◽

Paolo Piazza ◽

Mounia Alaoui-El-Azher ◽

Charles R. Rinaldo ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

B Lymphocytes ◽

T Cell Subsets ◽

Viral Reservoir ◽

Myeloid Dendritic Cells ◽

And Control ◽

Hiv 1

AbstractInsight into the establishment and maintenance of HIV-1 infection in resting CD4+ T cell subsets is critical for the development of therapeutics targeting the HIV-1 reservoir. Although the frequency of HIV-1 infection, as quantified by the frequency of HIV-1 DNA, is lower in CD4+ naïve T cells (TN) compared to the memory T cell subsets, recent studies have shown that TN cells harbor a large pool of replication-competent virus. Interestingly, however, TN cells are highly resistant to direct (cis) HIV-1 infection in vitro, in particular to R5-tropic HIV-1, as TN cells do not express CCR5. In this study, we investigated whether TN cells could be efficiently HIV-1 trans-infected by professional antigen-presenting B lymphocytes and myeloid dendritic cells (DC) in the absence of global T cell activation. We found that B cells, but not DC, have a unique ability to efficiently trans infect TN cells in vitro. In contrast, both B cells and DC mediated HIV-1 trans infection of memory and activated CD4+ T cells. Moreover, we found that TN isolated from HIV-1-infected nonprogressors (NP) harbor significantly disproportionately lower levels of HIV-1 DNA compared to TN isolated from progressors. This is consistent with our previous finding that APC derived from NP do not efficiently trans-infect CD4+ T cells due to alterations in APC cholesterol metabolism and cell membrane lipid raft organization. These findings support that B cell-mediated trans infection of TN cells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression.ImportanceThe latent human immunodeficiency virus type 1 (HIV-1) reservoir in persons on antiretroviral therapy represents a major barrier to a cure. Although most studies have focused on the HIV-1 reservoir in the memory T cell subset, replication competent HIV-1 has been isolated from naïve T cells, and CCR5-tropic HIV-1 has been recovered from CCR5negTN cells from ART-suppressed HIV-1-infected individuals. In this study, we showed that CCR5negTN cells are efficiently trans infected with R-5 tropic HIV-1 by B lymphocytes, but not by myeloid dendritic cells. Furthermore, we found that TN isolated from NP harbor no or significantly less copies of HIV-1 DNA compared to ART-suppressed progressors. These findings support that B cell-mediated trans infection of TN cells with HIV-1 has a more profound role than previously considered in establishing the viral reservoir and control of HIV-1 disease progression. Understanding the establishment and maintenance of the HIV-1 latent reservoir is fundamental for the design of effective treatments for viral eradication.

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Vaccination of Leukemia Patients with Autologous In Vitro Cultured Leukemia Dendritic Cells.

Blood ◽

10.1182/blood.v108.11.5190.5190 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5190-5190

Author(s):

Lu Yue ◽

Qi-Rong Geng ◽

Jian-Chuan Xia ◽

Hui-jie Fan ◽

Hai- Xu ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

T Cell ◽

Intravenous Injection ◽

T Cell Subsets ◽

Leukemia Cells ◽

P Values ◽

Dc Vaccine ◽

Ifn Γ

Abstract OBJECTIVE:To investigate the safety and immunomodulation effect of dendritic cells(DCs)vaccine to leukemia patients cultured in vitro from autologous leukemia cells. METHOD:Leukemic-dendritic cells were cultured from autologous bone marrow leukemia cells in vitro using combined cytokines. Patients received four administrations of autologous in vitro cultured leukemia-DCs by intravenous injection during chemotherapy intervals when obtain complete remission (CR), once a week for four times. Peripheral blood were collected to analyze the serum Th1/Th2 cytokines as IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α by cytokine bead array(CBA) analysis and T cell subpopulations by flow cytometric method (FCM). RESULTS:A total of 31 patients who are hematologically confirmed as leukemia received the DC vaccination therapy from December 2002 to October 2005. 20 patients can be evaluated. Firstly, autologous leukemic-dendritic cells were cultured in vitro successfully. Secondly vaccinations were well tolerated. No major toxicity occurred in any of the patients. Thirdly, serum cytokines were all elevated 24hs after the first administration of DC vaccination compared to those before that. And IL-2, IFN-γ, IL-4 and IL-6 have statistically significant increases with Z values −2.576, −2.033, −2.777, −2.053 and p values 0.010,0.042,0.005,0.040, respectively. Relative increase of the cytokine levels induced by DC vaccination show a trend of TH1 cytokines advantage, suggesting an enhancing of cellular immune response. T cell subsets significantly increase in CD4/CD8 ratio and CD56 proportion with Z values −2.040, −1.988 and P values 0.041, 0.043, respectively. CONCLUSIONS:Autologous leukemic-DCs could be generated in vitro from leukemia cells. And the intravenous injection of autologous L-DC vaccine is safe and feasible, and it could enhance the immune response in vivo to a certain degree.

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