IFN-γ activated JAK1 shifts CD40-induced cytokine profiles in human antigen-presenting cells toward high IL-12p70 and low IL-10 production

Interleukin (IL)-15 regulates the proliferative activity of the CD8+ T-cell pool in human immunodeficiency virus (HIV)-infected patients, thereby contributing to the maintenance of the CD8+ T-cell–mediated immune response against HIV in extravascular tissues, including the lung. However, the effects of IL-15 on antigen-presenting cells (APC) during HIV infection are still unclear. In this study, we evaluated whether IL-15 regulates the macrophage stimulatory pathways governing inflammatory events that take place in the lung of patients with HIV infection. As a first step we evaluated the in vitro effects of IL-15 on lung macrophages retrieved from the respiratory tract of eight normal subjects. Although macrophages from uninfected individuals expressed the IL-15 binding proteins (IL-15R and the common γc) at resting conditions, they did not express IL-15 messenger RNA (mRNA). However, a 24-hour stimulation with IL-15 induced the expression of interferon-γ (IFN-γ) and IL-15 itself, suggesting a role for this cytokine in the activation of the pulmonary macrophage pool during inflammation. As a confirmation of the role of IL-15 in this setting, at resting conditions, alveolar macrophages of patients with HIV infection and T-cell alveolitis expressed IL-15, IFN-γ, and IL-15 binding proteins; showed an upmodulation of costimulatory molecules, B7 and CD72, which are involved in the APC of macrophages; and behaved as effective accessory cells because they elicited a strong proliferation of T cells. The accessory effect was inhibited by pretreatment with anti-CD72, anti-B7 (CD80 and CD86), and anti–IL-15 monoclonal antibodies (MoAb). We then investigated the relationship between IL-15 and the expression of costimulatory molecules by macrophages. A 24-hour stimulation of IL-15R+/γc+ macrophages with IL-15 upregulated the expression of CD80 and CD86. The evidence that IL-15 upregulates the expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoattractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated defense mechanisms taking place in extravascular tissues of patients with HIV disease.

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Mycobacterium tuberculosis-Induced Gamma Interferon Production by Natural Killer Cells Requires Cross Talk with Antigen-Presenting Cells Involving Toll-Like Receptors 2 and 4 and the Mannose Receptor in Tuberculous Pleurisy

Infection and Immunity ◽

10.1128/iai.00381-07 ◽

2007 ◽

Vol 75 (11) ◽

pp. 5325-5337 ◽

Cited By ~ 39

Author(s):

Pablo Schierloh ◽

Noemí Yokobori ◽

Mercedes Alemán ◽

Verónica Landoni ◽

Laura Geffner ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Nk Cells ◽

Natural Killer ◽

Antigen Presenting Cells ◽

Mannose Receptor ◽

Gamma Interferon ◽

High Molecular Weight Fraction ◽

Tuberculous Pleurisy ◽

Ifn Γ ◽

Antigen Presenting

ABSTRACT Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis infection. In this study, we found that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early gamma interferon (IFN-γ) upon M. tuberculosis stimulation, leading us to investigate the mechanisms and molecules involved in this process. We show that the whole bacterium is the best inducer of IFN-γ, although a high-molecular-weight fraction of culture filtrate proteins from M. tuberculosis H37Rv and the whole-cell lysate also induce its expression. The mannose receptor seems to mediate the inhibitory effect of mannosylated lipoarabinomannan, and Toll-like receptor 2 and 4 agonists activate NK cells but do not induce IFN-γ like M. tuberculosis does. Antigen-presenting cells (APC) and NK cells bind M. tuberculosis, and although interleukin-12 is required, it is not sufficient to induce IFN-γ expression, indicating that NK cell-APC contact takes place. Indeed, major histocompatibility complex class I, adhesion, and costimulatory molecules as well as NK receptors regulate IFN-γ induction. The signaling pathway is partially inhibited by dexamethasone and sensitive to Ca2+ flux and cyclosporine. Inhibition of p38 and extracellular-regulated kinase mitogen-activated protein kinase pathways reduces the number of IFN-γ+ NK cells. Phosphorylated p38 (p-p38) is detected in ex vivo PF-NK cells, and M. tuberculosis triggers p-p38 in PF-NK cells at the same time that binding between NK and M. tuberculosis reaches its maximum value. Thus, interplay between M. tuberculosis and NK cells/APC triggering IFN-γ would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile.

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FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515574895 ◽

2015 ◽

Vol 21 (14) ◽

pp. 1811-1822 ◽

Cited By ~ 20

Author(s):

Felix Luessi ◽

Stefan Kraus ◽

Bettina Trinschek ◽

Steffen Lerch ◽

Robert Ploen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Healthy Subjects ◽

Ex Vivo ◽

Antigen Presenting Cells ◽

Direct Effects ◽

Quantitative Analyses ◽

Ifn Γ ◽

Multiple Sclerosis Patients ◽

Antigen Presenting

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. Conclusions: Our data indicate that fingolimod – apart from trapping lymphocytes in lymph nodes – exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

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Impact of antigen-presenting cells on cytokine profiles of human Th clones established after stimulation with Mycobacterium tuberculosis antigens.

Infection and Immunity ◽

10.1128/iai.63.5.2079-2081.1995 ◽

1995 ◽

Vol 63 (5) ◽

pp. 2079-2081 ◽

Cited By ~ 6

Author(s):

P Conradt ◽

S H Kaufmann

Keyword(s):

Mycobacterium Tuberculosis ◽

Antigen Presenting Cells ◽

Cytokine Profiles ◽

Antigen Presenting

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Selective Abrogation of Major Histocompatibility Complex Class II Expression on Extrahematopoietic Cells in Mice Lacking Promoter IV of the Class II Transactivator Gene

Journal of Experimental Medicine ◽

10.1084/jem.194.4.393 ◽

2001 ◽

Vol 194 (4) ◽

pp. 393-406 ◽

Cited By ~ 93

Author(s):

Jean-Marc Waldburger ◽

Tobias Suter ◽

Adriano Fontana ◽

Hans Acha-Orbea ◽

Walter Reith

Keyword(s):

Mhc Class Ii ◽

Antigen Presenting Cells ◽

Class Ii ◽

Thymic Epithelial Cells ◽

Class Ii Transactivator ◽

Ifn Γ ◽

Definition Of ◽

Antigen Presenting ◽

Mhcii Expression

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-γ–induced MHCII expression on a wide variety of non-bone marrow–derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4+ T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-γ–activated cells of the macrophage lineage. pIV−/− mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease.

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An Increase in Antimycobacterial Th1-Cell Responses by Prime-Boost Protocols of Immunization Does Not Enhance Protection against Tuberculosis

Infection and Immunity ◽

10.1128/iai.74.4.2128-2137.2006 ◽

2006 ◽

Vol 74 (4) ◽

pp. 2128-2137 ◽

Cited By ~ 79

Author(s):

Laleh Majlessi ◽

Marcela Simsova ◽

Zdenka Jarvis ◽

Priscille Brodin ◽

Marie-Jésus Rojas ◽

...

Keyword(s):

T Cells ◽

Interleukin 2 ◽

Antigen Presenting Cells ◽

Mycobacterial Infection ◽

Complete Sequence ◽

Th1 Cell ◽

Ifn Γ ◽

Vector Targeting ◽

Antigen Presenting

ABSTRACTBordetella pertussisadenylate cyclase (CyaA) toxoid is a powerful nonreplicative immunization vector targeting dendritic cells, which has already been used successfully in prophylactic and therapeutic vaccination in various preclinical animal models. Here, we investigated the potential of CyaA, harboring strong mycobacterial immunogens, i.e., the immunodominant regions of antigen 85A or the complete sequence of the 6-kDa early secreted antigenic target (ESAT-6) protein, to induce antimycobacterial immunity. By generating T-cell hybridomas or by using T cells from mice infected with mycobacteria, we first demonstrated that the in vitro delivery of 85A or ESAT-6 to antigen-presenting cells by CyaA leads to processing and presentation, by major histocompatibility complex class II molecules, of the same epitopes as those displayed upon mycobacterial infection. Importantly, compared to the recombinant protein alone, the presentation of ESAT-6 in vitro was 100 times more efficient upon its delivery to antigen-presenting cells in fusion to CyaA. Immunization with CyaA-85A or CyaA-ESAT-6 in the absence of any adjuvant induced strong antigen-specific lymphoproliferative, interleukin-2 (IL-2) and gamma interferon (IFN-γ) cytokine responses, in the absence of any IL-4 or IL-5 production. When used as boosters after priming with a BCG expressing ESAT-6, the CyaA-85A and CyaA-ESAT-6 proteins were able to strikingly increase the sensitivity and intensity of proliferative and Th1-polarized responses and notably the frequency of antigen-specific IFN-γ-producing CD4+T cells. However, immunization with these CyaA constructs as subunit vaccines alone or as boosters did not allow induction or improvement of protection againstMycobacterium tuberculosisinfection. These results question the broadly admitted correlation between the frequency of IFN-γ-producing CD4+T cells and the level of protection against tuberculosis.

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