<i><scp>M</scp>ycobacterium tuberculosis</i><scp>P</scp>st<scp>S</scp>1 amplifies <scp>IFN</scp>‐γ and induces <scp>IL</scp>‐17/<scp>IL</scp>‐22 responses by unrelated memory <scp>CD</scp>4<sup>+</sup><scp>T</scp> cells via dendritic cell activation

Palma, Carla; Schiavoni, Giovanna; Abalsamo, Laura; Mattei, Fabrizio; Piccaro, Giovanni; Sanchez, Massimo; Fernández, Carmen; Singh, Mahavir; Gabriele, Lucia

doi:10.1002/eji.201243245

Cited by 22 publications

(12 citation statements)

References 55 publications

(96 reference statements)

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“…2D). Previously, IL-23 and IL-6 dependence of Th17 differentiation in vivo and its influence on Th1 differentiation has been reported [35–40]. Therefore we investigated the role of Rictor −/− DC-secreted IL-23 and IL-6 in the promotion of Th1 and Th17 cells.…”

Section: Resultsmentioning

confidence: 93%

mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo

Raïch‐Regué

Rosborough

Watson

et al. 2015

The Journal of Immunology

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The mammalian/mechanistic target of rapamycin (mTOR) is a key integrative kinase that functions in two independent complexes, mTOR complex (mTORC) 1 and mTORC2. In contrast to the well-defined role of mTORC1 in dendritic cells (DC), little is known about the function of mTORC2. Here, we demonstrate for the first time an enhanced ability of mTORC2-deficient myeloid DC to stimulate and polarize allogeneic T cells. We show that activated bone marrow-derived DC from conditional Rictor−/− mice exhibit lower co-inhibitory B7-H1 molecule expression independently of the stimulus and enhanced IL-6, TNFα, IL-12p70 and IL-23 production following TLR4 ligation. Accordingly, TLR4-activated Rictor−/− DC display augmented allogeneic T cell stimulatory ability, expanding IFN-γ+ and IL-17+, but not IL-10+ or CD4+Foxp3+ regulatory T cells in vitro. A similar DC profile was obtained by stimulating Dectin-1 (C-type lectin family member) on Rictor−/− DC. Using novel CD11c-specific Rictor−/− mice, we confirm the alloreactive Th1 and Th17 cell-polarizing ability of endogenous mTORC2-deficient DC after TLR4 ligation in vivo. Furthermore, we demonstrate that pro-inflammatory cytokines produced by Rictor−/− DC after LPS stimulation are key in promoting Th1/Th17 responses. These data establish that mTORC2 activity restrains conventional DC pro-inflammatory capacity and their ability to polarize T cells following TLR and non-TLR stimulation. Our findings provide new insight into the role of mTORC2 in regulating DC function and may have implications for emerging therapeutic strategies that target mTOR in cancer, infectious diseases, and transplantation.

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Section: Resultsmentioning

confidence: 93%

mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo

Raïch‐Regué

Rosborough

Watson

et al. 2015

The Journal of Immunology

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“…In addition, specific CD8 + T-lymphocytes were shown to produce IFN-g during an infection with a nonrelated pathogen [30], and furthermore, CD4 + T-lymphocytes can produce IFN-g upon stimulation with IL-12 in an antigen-independent manner [31,32]. When PstS1-induced memory CD4 + T-lymphocytes were incubated with activated DCs, in the absence of a pathogen, increased production of IFN-g, IL-17, and IL-22 by the memory T-lymphocytes was observed, which was partly dependent on IL-6 production of the DCs [34]. When PstS1-induced memory CD4 + T-lymphocytes were incubated with activated DCs, in the absence of a pathogen, increased production of IFN-g, IL-17, and IL-22 by the memory T-lymphocytes was observed, which was partly dependent on IL-6 production of the DCs [34].…”

Section: Discussionmentioning

confidence: 98%

Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity

Arts

Blok

Aaby

et al. 2015

Journal of Leukocyte Biology

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BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition receptors and histone methylation markers were assessed. The in vivo effects of γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γBCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited.

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“…The role of IL-17- and IL-22-producing CD4+ T cells has been investigated in animal models and whether these cells are protective or detrimental needs to be further investigated(28–30). While murine IL-17 produced by CD4+ T cells helps to recruit IFN-γ-producing cells and to control Mtb infection(29), Th17 cells could correlate with either anti-Mtb response or TB severity(31–33). IL-22-producing cells can limit intracellular Mtb growth in vitro (30), but their role in Mtb-infected individuals needs to be further investigated.…”

Section: Introductionmentioning

confidence: 99%

CD4+ T Cells Contain Early Extrapulmonary Tuberculosis (TB) Dissemination and Rapid TB Progression and Sustain Multieffector Functions of CD8+ T and CD3− Lymphocytes: Mechanisms of CD4+ T Cell Immunity

Shan

Huang

Chen

et al. 2014

The Journal of Immunology

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The possibility that CD4+ T cells can act as “innate-like” cells to contain very-early M. tuberculosis (Mtb) dissemination and function as master helpers to sustain multiple effector functions of CD8+ T cells and CD3-negative lymphocytes during development of adaptive immunity against primary tuberculosis(TB) has not been demonstrated. We showed that pulmonary Mtb infection of CD4-depleted macaques surprisingly led to very-early extrathoracic Mtb dissemination, whereas CD4 deficiency clearly resulted in rapid TB progression. CD4 depletion during Mtb infection revealed the ability of CD8+ T cells to compensate and rapidly differentiate to Th17-like/Th1-like, and cytotoxic-like effectors, but these effector functions were subsequently unsustainable due to CD4 deficiency. While CD3-negative non-T lymphocytes in presence of CD4+ T cells developed predominant Th22-like and NK-like (perforin production) responses to Mtb infection, CD4 depletion abrogated these Th22-/NK-like effector functions and favored IL-17 production by CD3-negative lymphocytes. CD4-depleted macaques exhibited no or few pulmonary T effector cells constitutively producing IFN-γ, TNFα, IL-17, IL-22, and perforin at the endpoint of more severe TB, but presented pulmonary IL-4+ T effectors. TB granulomas in CD4-depleted macaques contained fewer IL-22+ and perforin+ cells despite presence of IL-17+ and IL-4+ cells. These results implicate previously-unknown “innate-like” ability of CD4+ T cells to contain extrathoracic Mtb dissemination at very early stage. Data also suggest that CD4+ T cells are required to sustain multiple effector functions of CD8+ T cells and CD3-negative lymphocytes and to prevent rapid TB progression during Mtb infection of nonhuman primates.

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Mycobacterium tuberculosisPstS1 amplifies IFN‐γ and induces IL‐17/IL‐22 responses by unrelated memory CD4⁺T cells via dendritic cell activation

Abstract: The immunological mechanisms that modulate protection duringAdditional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 22 publications

References 55 publications

mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo

mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo

Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity

CD4+ T Cells Contain Early Extrapulmonary Tuberculosis (TB) Dissemination and Rapid TB Progression and Sustain Multieffector Functions of CD8+ T and CD3− Lymphocytes: Mechanisms of CD4+ T Cell Immunity

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Mycobacterium tuberculosisPstS1 amplifies IFN‐γ and induces IL‐17/IL‐22 responses by unrelated memory CD4+T cells via dendritic cell activation

Abstract: The immunological mechanisms that modulate protection duringAdditional supporting information may be found in the online version of this article at the publisher's web-site

Cited by 22 publications

References 55 publications

mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo

mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo

Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity

CD4+ T Cells Contain Early Extrapulmonary Tuberculosis (TB) Dissemination and Rapid TB Progression and Sustain Multieffector Functions of CD8+ T and CD3− Lymphocytes: Mechanisms of CD4+ T Cell Immunity

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Mycobacterium tuberculosisPstS1 amplifies IFN‐γ and induces IL‐17/IL‐22 responses by unrelated memory CD4⁺T cells via dendritic cell activation