The Orally Available, Synthetic Ether Lipid Edelfosine Inhibits T Cell Proliferation and Induces a Type I Interferon Response

AbstractInfection with the human immunodeficiency virus type-1 (HIV) results in acute and progressive numeric loss of CD4+ T-helper cells and functional impairment of T-cell responses. The mechanistic basis of the functional impairment of the surviving cells is not clear. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme that inhibits T-cell proliferation by catabolizing the essential amino acid tryptophan (Trp) into the kynurenine (kyn) pathway. Here, we show that IDO mRNA expression is elevated in peripheral blood mononuclear cells (PBMCs) from HIV+ patients compared with uninfected healthy controls (HCs), and that in vitro inhibition of IDO with the competitive blocker 1-methyl tryptophan (1-mT) results in increased CD4+ T-cell proliferative response in PBMCs from HIV-infected patients. We developed an in vitro model in which exposure of PBMCs from HCs to either infectious or noninfectious, R5- or X4-tropic HIV induced IDO in plasmacytoid dendritic cells (pDCs). HIV-induced IDO was not inhibited by blocking antibodies against interferon type I or type II, which, however, induced IDO in pDCs when added to PBMC cultures. Blockade of gp120/CD4 interactions with anti-CD4 Ab inhibited HIV-mediated IDO induction. Thus, induction of IDO in pDCs by HIV may contribute to the T-cell functional impairment observed in HIV/AIDS by a non–interferon-dependent mechanism.

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Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

10.1101/398081 ◽

2018 ◽

Author(s):

Shaylynn Miller ◽

Patrick Coit ◽

Elizabeth Gensterblum-Miller ◽

Paul Renauer ◽

Nathan C Kilian ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Mrna Levels ◽

Healthy Controls ◽

Genome Wide

AbstractObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. Co-incubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

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The NS2 Protein of Human Respiratory Syncytial Virus Suppresses the Cytotoxic T-Cell Response as a Consequence of Suppressing the Type I Interferon Response

Journal of Virology ◽

10.1128/jvi.01773-06 ◽

2006 ◽

Vol 80 (20) ◽

pp. 10286-10286

Author(s):

Alexander Kotelkin ◽

Igor M. Belyakov ◽

Lijuan Yang ◽

Jay A. Berzofsky ◽

Peter L. Collins ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

T Cell ◽

Cell Response ◽

Type I Interferon ◽

T Cell Response ◽

Human Respiratory Syncytial Virus ◽

Interferon Response ◽

Cytotoxic T Cell ◽

Type I ◽

Syncytial Virus

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HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.02182-16 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 16

Author(s):

Juan García-Arriaza ◽

Beatriz Perdiguero ◽

Jonathan L. Heeney ◽

Michael S. Seaman ◽

David C. Montefiori ◽

...

Keyword(s):

T Cell ◽

Nonhuman Primates ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Vaccine Candidates ◽

Aids Vaccine ◽

Clade C ◽

Hiv 1 ◽

Hiv Aids

ABSTRACT The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4+ and CD8+ T cells, here we compared the HIV-1-specific immunogenicity elicited in nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of the K1L and C7L vaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral gene B19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4) and booster doses with NYVAC-C-KC vectors plus the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+ and CD8+ T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4+ and CD8+ T cells, the induction of some cytokines, and the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions. IMPORTANCE It is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion in B19R inducing a trend toward a higher magnitude of CD4+ and CD8+ T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.

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Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant

Journal of Experimental Medicine ◽

10.1084/jem.20090247 ◽

2009 ◽

Vol 206 (7) ◽

pp. 1589-1602 ◽

Cited By ~ 398

Author(s):

M. Paula Longhi ◽

Christine Trumpfheller ◽

Juliana Idoyaga ◽

Marina Caskey ◽

Ines Matos ◽

...

Keyword(s):

T Cell ◽

Type I Interferon ◽

Host Cells ◽

Interferon Response ◽

Type I ◽

Type I Ifn ◽

Protein Vaccine ◽

Adaptive Responses ◽

Cell Repertoire ◽

Gag Protein

Relative to several other toll-like receptor (TLR) agonists, we found polyinosinic:polycytidylic acid (poly IC) to be the most effective adjuvant for Th1 CD4+ T cell responses to a dendritic cell (DC)–targeted HIV gag protein vaccine in mice. To identify mechanisms for adjuvant action in the intact animal and the polyclonal T cell repertoire, we found poly IC to be the most effective inducer of type I interferon (IFN), which was produced by DEC-205+ DCs, monocytes, and stromal cells. Antibody blocking or deletion of type I IFN receptor showed that IFN was essential for DC maturation and development of CD4+ immunity. The IFN-AR receptor was directly required for DCs to respond to poly IC. STAT 1 was also essential, in keeping with the type I IFN requirement, but not type II IFN or IL-12 p40. Induction of type I IFN was mda5 dependent, but DCs additionally used TLR3. In bone marrow chimeras, radioresistant and, likely, nonhematopoietic cells were the main source of IFN, but mda5 was required in both marrow–derived and radioresistant host cells for adaptive responses. Therefore, the adjuvant action of poly IC requires a widespread innate type I IFN response that directly links antigen presentation by DCs to adaptive immunity.

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Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-214323 ◽

2019 ◽

Vol 78 (4) ◽

pp. 519-528 ◽

Cited By ~ 5

Author(s):

Shaylynn Miller ◽

Pei-Suen Tsou ◽

Patrick Coit ◽

Elizabeth Gensterblum-Miller ◽

Paul Renauer ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

Mrna Levels ◽

Healthy Controls ◽

Genome Wide

ObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from patients with lupus and controls and investigated the functional relevance of some of these changes in lupus.MethodsGenome-wide DNA methylation of lupus and age, sex and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR. Inhibiting STAT1 and CIITA was performed using fludarabine and CIITA siRNA, respectively.ResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared with healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFNα upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFNα. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFNα in lupus CD8+ T cells, but not healthy controls. CIITA knockdown and STAT1 inhibition experiments revealed that HLA-DRB1 expression in lupus CD8+ T cells is dependent on CIITA and STAT1 signalling. Coincubation of naïve CD4+ T cells with IFNα-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69 and cytokine production, in patients with lupus but not in healthy controls. This can be blocked by neutralising antibodies targeting HLA-DR.ConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFNα in patients with lupus. A possible pathogenic role for CD8+ T cells in lupus that is dependent on a high type-I interferon environment and epigenetic priming warrants further characterisation.

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Absence of cGAS-mediated type I IFN responses in HIV-1–infected T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2002481117 ◽

2020 ◽

Vol 117 (32) ◽

pp. 19475-19486

Author(s):

Carina Elsner ◽

Aparna Ponnurangam ◽

Julia Kazmierski ◽

Thomas Zillinger ◽

Jenny Jansen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Plasmid Dna ◽

Type I Interferon ◽

Interferon Response ◽

Type I ◽

T Cell Lines ◽

Hiv 1 ◽

Dependent Type

The DNA sensor cGAS catalyzes the production of the cyclic dinucleotide cGAMP, resulting in type I interferon responses. We addressed the functionality of cGAS-mediated DNA sensing in human and murine T cells. Activated primary CD4+T cells expressed cGAS and responded to plasmid DNA by upregulation of ISGs and release of bioactive interferon. In mouse T cells, cGAS KO ablated sensing of plasmid DNA, and TREX1 KO enabled cells to sense short immunostimulatory DNA. Expression ofIFIT1andMX2was downregulated and upregulated in cGAS KO and TREX1 KO T cell lines, respectively, compared to parental cells. Despite their intact cGAS sensing pathway, human CD4+T cells failed to mount a reverse transcriptase (RT) inhibitor-sensitive immune response following HIV-1 infection. In contrast, infection of human T cells with HSV-1 that is functionally deficient for the cGAS antagonist pUL41 (HSV-1ΔUL41N) resulted in a cGAS-dependent type I interferon response. In accordance with our results in primary CD4+T cells, plasmid challenge or HSV-1ΔUL41N inoculation of T cell lines provoked an entirely cGAS-dependent type I interferon response, including IRF3 phosphorylation and expression of ISGs. In contrast, no RT-dependent interferon response was detected following transduction of T cell lines with VSV-G-pseudotyped lentiviral or gammaretroviral particles. Together, T cells are capable to raise a cGAS-dependent cell-intrinsic response to both plasmid DNA challenge or inoculation with HSV-1ΔUL41N. However, HIV-1 infection does not appear to trigger cGAS-mediated sensing of viral DNA in T cells, possibly by revealing viral DNA of insufficient quantity, length, and/or accessibility to cGAS.

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