scholarly journals Type I Interferons and Malaria: A Double-Edge Sword Against a Complex Parasitic Disease

2020 ◽  
Vol 10 ◽  
Author(s):  
Xiao He ◽  
Lu Xia ◽  
Keyla C. Tumas ◽  
Jian Wu ◽  
Xin-Zhuan Su
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Plasmodium Yoelii ◽  
Type I Interferons ◽  
Complex Life Cycle ◽  
Type I ◽  
Malaria Parasites ◽  
Cytokines And Chemokines

Type I interferons (IFN-Is) are important cytokines playing critical roles in various infections, autoimmune diseases, and cancer. Studies have also shown that IFN-Is exhibit ‘conflicting’ roles in malaria parasite infections. Malaria parasites have a complex life cycle with multiple developing stages in two hosts. Both the liver and blood stages of malaria parasites in a vertebrate host stimulate IFN-I responses. IFN-Is have been shown to inhibit liver and blood stage development, to suppress T cell activation and adaptive immune response, and to promote production of proinflammatory cytokines and chemokines in animal models. Different parasite species or strains trigger distinct IFN-I responses. For example, a Plasmodium yoelii strain can stimulate a strong IFN-I response during early infection, whereas its isogenetic strain does not. Host genetic background also greatly influences IFN-I production during malaria infections. Consequently, the effects of IFN-Is on parasitemia and disease symptoms are highly variable depending on the combination of parasite and host species or strains. Toll-like receptor (TLR) 7, TLR9, melanoma differentiation-associated protein 5 (MDA5), and cyclic GMP-AMP synthase (cGAS) coupled with stimulator of interferon genes (STING) are the major receptors for recognizing parasite nucleic acids (RNA/DNA) to trigger IFN-I responses. IFN-I levels in vivo are tightly regulated, and various novel molecules have been identified to regulate IFN-I responses during malaria infections. Here we review the major findings and progress in ligand recognition, signaling pathways, functions, and regulation of IFN-I responses during malaria infections.

scholarly journals Type I Interferon-mediated Stimulation of T Cells by CpG DNA

1998 ◽  
Vol 188 (12) ◽  
pp. 2335-2342 ◽  
Author(s):  
Siquan Sun ◽  
Xiaohong Zhang ◽  
David F. Tough ◽  
Jonathan Sprent
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Type I Interferons ◽  
Type I ◽  
Cpg Dna ◽  
Stimulation Of

Immunostimulatory DNA and oligodeoxynucleotides containing unmethylated CpG motifs (CpG DNA) are strongly stimulatory for B cells and antigen-presenting cells (APCs). We report here that, as manifested by CD69 and B7-2 upregulation, CpG DNA also induces partial activation of T cells, including naive-phenotype T cells, both in vivo and in vitro. Under in vitro conditions, CpG DNA caused activation of T cells in spleen cell suspensions but failed to stimulate highly purified T cells unless these cells were supplemented with APCs. Three lines of evidence suggested that APC-dependent stimulation of T cells by CpG DNA was mediated by type I interferons (IFN-I). First, T cell activation by CpG DNA was undetectable in IFN-IR−/− mice. Second, in contrast to normal T cells, the failure of purified IFN-IR−/− T cells to respond to CpG DNA could not be overcome by adding normal IFN-IR+ APCs. Third, IFN-I (but not IFN-γ) caused the same pattern of partial T cell activation as CpG DNA. Significantly, T cell activation by IFN-I was APC independent. Thus, CpG DNA appeared to stimulate T cells by inducing APCs to synthesize IFN-I, which then acted directly on T cells via IFN-IR. Functional studies suggested that activation of T cells by IFN-I was inhibitory. Thus, exposing normal (but not IFN-IR−/−) T cells to CpG DNA in vivo led to reduced T proliferative responses after TCR ligation in vitro.

scholarly journals Early and Strong Immune Responses Are Associated with Control of Viral Replication and Recovery in Lassa Virus-Infected Cynomolgus Monkeys

2009 ◽  
Vol 83 (11) ◽  
pp. 5890-5903 ◽  
Author(s):  
Sylvain Baize ◽  
Philippe Marianneau ◽  
Philippe Loth ◽  
Stéphanie Reynard ◽  
Alexandra Journeaux ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Responses ◽  
Viral Replication ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Type I Interferons ◽  
Lassa Virus ◽  
Type I ◽  
Cynomolgus Monkeys

ABSTRACT Lassa virus causes a hemorrhagic fever endemic in West Africa. The pathogenesis and the immune responses associated with the disease are poorly understood, and no vaccine is available. We followed virological, pathological, and immunological markers associated with fatal and nonfatal Lassa virus infection of cynomolgus monkeys. The clinical picture was characterized by fever, weight loss, depression, and acute respiratory syndrome. Transient thrombocytopenia and lymphopenia, lymphadenopathy, splenomegaly, infiltration of mononuclear cells, and alterations of the liver, lungs, and endothelia were observed. Survivors exhibited fewer lesions and a lower viral load than nonsurvivors. Although all animals developed strong humoral responses, antibodies appeared more rapidly in survivors and were directed against GP1, GP2, and NP. Type I interferons were detected early after infection in survivors but only during the terminal stages in fatalities. The mRNAs for CXCL10 (IP-10) and CXCL11 (I-TAC) were abundant in peripheral blood mononuclear cells and lymph nodes from infected animals, but plasma interleukin-6 was detected only in fatalities. In survivors, high activated-monocyte counts were followed by a rise in the total number of circulating monocytes. Activated T lymphocytes circulated in survivors, whereas T-cell activation was low and delayed in fatalities. In vitro stimulation with inactivated Lassa virus induced activation of T lymphocytes from all infected monkeys, but only lymphocytes from survivors proliferated. Thus, early and strong immune responses and control of viral replication were associated with recovery, whereas fatal infection was characterized by major alterations of the blood formula and, in organs, weak immune responses and uncontrolled viral replication.

scholarly journals A Contribution of Mouse Dendritic Cell–Derived IL-2 for NK Cell Activation

2004 ◽  
Vol 200 (3) ◽  
pp. 287-295 ◽  
Author(s):  
Francesca Granucci ◽  
Ivan Zanoni ◽  
Norman Pavelka ◽  
Serani L.H. van Dommelen ◽  
Christopher E. Andoniou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Type I Interferons ◽  
Efficient Production ◽  
Type I ◽  
New Information

Dendritic cells (DCs) play a predominant role in activation of natural killer (NK) cells that exert their functions against pathogen-infected and tumor cells. Here, we used a murine model to investigate the molecular mechanisms responsible for this process. Two soluble molecules produced by bacterially activated myeloid DCs are required for optimal priming of NK cells. Type I interferons (IFNs) promote the cytotoxic functions of NK cells. IL-2 is necessary both in vitro and in vivo for the efficient production of IFNγ, which has an important antimetastatic and antibacterial function. These findings provide new information about the mechanisms that mediate DC–NK cell interactions and define a novel and fundamental role for IL-2 in innate immunity.

scholarly journals Tofacitinib Ameliorates Lupus Through Suppression of T Cell Activation Mediated by TGF-Beta Type I Receptor

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Yan ◽  
Weiwei Chen ◽  
Hua Song ◽  
Xianming Long ◽  
Zhuoya Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Type I ◽  
Dependent Manner ◽  
Dsdna Antibody

Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4+ T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. In vitro, the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation in vivo. TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.

scholarly journals Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

2019 ◽  
Vol 2 (1) ◽  
pp. e201800282 ◽  
Author(s):  
Takayuki Imanishi ◽  
Midori Unno ◽  
Wakana Kobayashi ◽  
Natsumi Yoneda ◽  
Satoshi Matsuda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Physiological Role ◽  
Type I ◽  
Tcr Signaling ◽  
Reciprocal Regulation ◽  
Cell Functions

Stimulator of interferon genes (STING) plays a key role in detecting cytosolic DNA and induces type I interferon (IFN-I) responses for host defense against pathogens. Although T cells highly express STING, its physiological role remains unknown. Here, we show that costimulation of T cells with the STING ligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1 activation and sustained activation of IRF3 are required for cGAMP-induced IFN-I production, and the mTORC1 activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1 inhibition in response to costimulation depends on IRF3 and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STING stimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T-cell functions.

scholarly journals Y-RNAs Lead an Endogenous Program of RIG-I Agonism Mobilized upon RNA Virus Infection and Targeted by HIV

2019 ◽  
Author(s):  
Nicolas Vabret ◽  
Valérie Najburg ◽  
Alexander Solovyov ◽  
Petr Šulc ◽  
Sreekumar Balan ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Rna Virus ◽  
Type I ◽  
Endogenous Ligands ◽  
Rna Triphosphatase ◽  
Molecular Patterns ◽  
Hiv 1

AbstractPattern recognition receptors (PRRs) protect against host invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. While microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation during viral infection remain overlooked. In this work, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by a positive-sense RNA virus, a negative-sense RNA virus or a retrovirus. We found that several endogenous RNAs transcribed by RNA polymerase 3 (Pol3) specifically engage RLRs, and in particular the family of small non-coding repeats Y-RNAs, which presents the highest affinity as RIG-I ligands. We show that this recognition is dependent on Y-RNA mimicking viral secondary structure and its 5’-triphosphate extremity. Further, we found that HIV-1 infection triggers a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, leading to an increase of Y-RNA 5’-triphosphorylation that enables their immunogenicity. Importantly, we show that altering DUSP11 expression is sufficient to induce a type-I interferon and T cell activation transcriptional program associated with HIV-1 infection. Overall, our work uncovers the critical contribution of endogenous repeat RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.

scholarly journals Novel APC-like properties of human NK cells directly regulate T cell activation

2015 ◽  
Author(s):  
Jacob Hanna ◽  
Ofer Mandelboim
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Mhc Class Ii ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Antigen Uptake

Initiation of the adaptive immune response is dependent on the priming of naive T cells by APCs. Proteomic analysis of unactivated and activated human NK cell membrane-enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since they upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules. Furthermore, by manipulating antigen administration, we show that NK cells possess multiple independent unique pathways for antigen uptake. These results highlight NK cell-mediated cytotoxicity and specific ligand recognition by cell surface-activating receptors on NK cells as unique mechanisms for antigen capturing and presentation. In addition, we analyzed the T cell-activating potential of human NK cells derived from different clinical conditions, such as inflamed tonsils and noninfected and CMV-infected uterine decidual samples, and from transporter-associated processing antigen 2–deficient patients. This in vivo analysis revealed that proinflammatory, but not immune-suppressive, microenvironmental requirements can selectively dictate upregulation of T cell-activating molecules on NK cells. Taken together, these observations offer new and unexpected insights into the direct interactions between NK and T cells and suggest novel APC-like activating functions for human NK cells.

scholarly journals Non-Pathogenic Mopeia Virus Induces More Robust Activation of Plasmacytoid Dendritic Cells than Lassa Virus

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 287 ◽  
Author(s):  
Justine Schaeffer ◽  
Stéphanie Reynard ◽  
Xavier Carnec ◽  
Natalia Pietrosemoli ◽  
Marie-Agnès Dillies ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasmacytoid Dendritic Cells ◽  
Health Concern ◽  
Lassa Virus ◽  
Type I ◽  
Viral Haemorrhagic Fever

Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection.

scholarly journals Murlentamab, a Low Fucosylated Anti-Müllerian Hormone Type II Receptor (AMHRII) Antibody, Exhibits Anti-Tumor Activity through Tumor-Associated Macrophage Reprogrammation and T Cell Activation

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1845
Author(s):  
Mélissa Prat ◽  
Marie Salon ◽  
Thibault Allain ◽  
Olivier Dubreuil ◽  
Grégory Noël ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Advanced Cancer Patients ◽  
Effector Cells ◽  
Tumor Associated Macrophage ◽  
Cytokines And Chemokines ◽  
And Shifts ◽  
Anti Tumor Activity

AMHRII, the anti-Müllerian hormone receptor, is selectively expressed in normal sexual organs but is also re-expressed in gynecologic cancers. Hence, we developed murlentamab, a humanized glyco-engineered anti-AMHRII monoclonal antibody currently in clinical trial. Low-fucosylated antibodies are known to increase the antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) potency of effector cells, but some preliminary results suggest a more global murlentamab-dependent activation of the immune system. In this context, we demonstrate here that the murlentamab opsonization of AMHRII-expressing ovarian tumor cells, in the presence of unstimulated- or tumor-associated macrophage (TAM)-like macrophages, significantly promotes macrophage-mediated ADCC and shifts the whole microenvironment towards a pro-inflammatory and anti-tumoral status, thus triggering anti-tumor activity. We also report that murlentamab orients both unstimulated- and TAM-like macrophages to an M1-like phenotype characterized by a strong expression of co-stimulation markers, pro-inflammatory cytokines and chemokines, favoring T cell recruitment and activation. Moreover, we show that murlentamab treatment shifts CD4+ Th1/Th2 balance towards a Th1 response and activates CD8+ T cells. Altogether, these results suggest that murlentamab, through naïve macrophage orientation and TAM reprogrammation, stimulates the anti-tumor adaptive immune response. Those mechanisms might contribute to the sustained clinical benefit observed in advanced cancer patients treated with murlentamab. Finally, the enhanced murlentamab activity in combination with pembrolizumab opens new therapeutic perspectives.

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