Peter Klucar

Baylor University

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Peter F. Barnes

The University of Texas Health Science Center at Tyler

Homayoun Shams

The University of Texas Health Science Center at Tyler

Buka Samten

The University of Texas Health Science Center at Tyler

Benjamin Wizel

Dynavax Technologies (United States)

Stephen E. Weis

University of North Texas

Gérard Zurawski

Baylor Scott & White Health

Sandra Zurawski

Institut de Recherche Vaccinale

Hassan Safi

Rutgers, The State University of New Jersey

Ramakrishna Vankayalapati

The University of Texas Health Science Center at Tyler

Patrick K. Moonan

Centers for Disease Control and Prevention

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Inserm

Baylor University

Institut de Recherche Vaccinale

The University of Texas Health Science Center at Tyler

National Institutes of Health

Commissariat à l'Énergie Atomique et aux Énergies Alternatives

Assistance Publique – Hôpitaux de Paris

Baylor Institute for Rehabilitation

CEA Paris-Saclay

Université Paris-Saclay

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NK Cells Regulate CD8+ T Cell Effector Function in Response to an Intracellular Pathogen

The Journal of Immunology (2004)

Ramakrishna Vankayalapati Peter Klucar Benjamin Wizel Stephen E. Weis Buka Samten

Abstract We studied the role of NK cells in regulating human CD8+ T cell effector function against mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Depletion of NK cells from PBMC of healthy tuberculin reactors reduced the frequency of M. tuberculosis-responsive CD8+IFN-γ+ cells and decreased their capacity to lyse M. tuberculosis-infected monocytes. The frequency of CD8+IFN-γ+cells was restored by soluble factors produced by activated NK cells and was dependent on IFN-γ, IL-15, and IL-18. M. tuberculosis-activated NK cells produced IFN-γ, activated NK cells stimulated infected monocytes to produce IL-15 and IL-18, and production of IL-15 and IL-18 were inhibited by anti-IFN-γ. These findings suggest that NK cells maintain the frequency of M. tuberculosis-responsive CD8+IFN-γ+ T cells by producing IFN-γ, which elicits secretion of IL-15 and IL-18 by monocytes. These monokines in turn favor expansion of Tc1 CD8+ T cells. The capacity of NK cells to prime CD8+ T cells to lyse M. tuberculosis-infected target cells required cell-cell contact between NK cells and infected monocytes and depended on interactions between the CD40 ligand on NK cells and CD40 on infected monocytes. NK cells link the innate and the adaptive immune responses by optimizing the capacity of CD8+ T cells to produce IFN-γ and to lyse infected cells, functions that are critical for protective immunity against M. tuberculosis and other intracellular pathogens.

Janus kinase 3

10.4049/jimmunol.172.1.130

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Citations (165)

The role of human Dectin-1 in eliciting antigen specific CD8+ T cell responses (130.35)

The Journal of Immunology (2010)

Ling Ni Xiaohua Li Ingrid Gayet Dorothée Duluc Peter Klucar

Abstract Dectin-1 recognizing fungal pathogens and mycobacteria, delivers intracellular signals to activate DCs. Here we report that Dectin-1 expressed on human DCs possesses unique immunological function that potentiates antigen-specific CD8+ T cell responses. We first generated an agonistic anti-Dectin-1 monoclonal antibody (mAb), which recognized Leu192-Asn202 in Dectin-1 and efficiently bound to both in vitro monocyte-derived DCs and in vivo CD1c+ skin dermal DCs, but not Langerin cells. Syk-dependent activation by anti-Dectin-1 mAb induced DCs to upregulate T cell costimulatory molecules, particularly CD70 and 4-1BBL, as well as cytokines and chemokines. This signaling via Dectin-1 allowed DCs to potentiate both memory and naïve CD8+ T cell responses by promoting their expansions and functional activities. Furthermore, both neo- and non-self-antigens delivered to DCs via Dectin-1 resulted in potent antigen-specific CD8+ T cell responses. This was largely dependent on CD70 and 4-1BBL upregulated by the signaling via Dectin-1. We also demonstrated that Dectin-1-mediated activation of DCs did not promote Foxp3+ and IL-10-producing regulatory CD4+ T cell responses, but potentiated CD4+ helper T cell function for inducing effector CD8+ T cells. We conclude that Dectin-1 on human DCs has unique function for eliciting antigen-specific CD8+ T cell responses by taking up antigens and delivering intracellular signals favoring effector CD8+ T cell responses.

10.4049/jimmunol.184.supp.130.35

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Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Claire-Maëlle Fovet Lev Stimmer Vanessa Contreras Philippe Horellou Audrey Hubert

Abstract To study the effect of vaccination on tolerization to the myelin antigen MOG we used a macaque model of experimental autoimmune encephalitis (EAE) in which immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) elicits brain inflammation and demyelination mediated by MOG-specific autoreactive CD4+ T lymphocytes and anti-MOG IgG. For antigen targeting to tolerizing antigen presenting cells, we used a recombinant antibody directed to the Dendritic Cells (DC)-Asialoglycoprotein receptor (DC-ASGPR). The intradermal administration of an anti-DC-ASGPR-MOG fusion protein, but not a control anti-DC-ASGPR-PSA (prostate specific antigen) protein, protected monkeys committed to develop EAE. Although effective treatment did not modify anti-MOG IgG production, it prevented the CD4+ T lymphocyte activation and pro-inflammatory cytokine production. Moreover, animals treated with anti-DC-ASGPR-MOG experienced a rise of MOG-specific CD4+CD25+FOXP3+CD39+ regulatory T cells as well as a TGF β 1, TGF β 2 and IL-8 upsurge after rhMOG re-immunization. Our results indicate that the pathogenicity of autoantibodies directed to MOG is mitigated in the presence of MOG-specific regulatory lymphocytes. This vaccination scheme appears suitable to treat relapsing autoimmune diseases with identified autoantigens such as that harboring anti-MOG or anti-AQP4 autoantibodies.

Myelin oligodendrocyte glycoprotein

Peripheral tolerance

10.1101/571828

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CREB, ATF, and AP-1 Transcription Factors Regulate IFN-γ Secretion by Human T Cells in Response to Mycobacterial Antigen

The Journal of Immunology (2008)

Buka Samten James C. Townsend Steven E. Weis Anindita Bhoumik Peter Klucar

IFN-gamma production by T cells is pivotal for defense against many pathogens, and the proximal promoter of IFN-gamma, -73 to -48 bp upstream of the transcription start site, is essential for its expression. However, transcriptional regulation mechanisms through this promoter in primary human cells remain unclear. We studied the effects of cAMP response element binding protein/activating transcription factor (CREB/ATF) and AP-1 transcription factors on the proximal promoter of IFN-gamma in human T cells stimulated with Mycobacterium tuberculosis. Using EMSA, supershift assays, and promoter pulldown assays, we demonstrated that CREB, ATF-2, and c-Jun, but not cyclic AMP response element modulator, ATF-1, or c-Fos, bind to the proximal promoter of IFN-gamma upon stimulation, and coimmunoprecipitation indicated the possibility of interaction among these transcription factors. Chromatin immunoprecipitation confirmed the recruitment of these transcription factors to the IFN-gamma proximal promoter in live Ag-activated T cells. Inhibition of ATF-2 activity in T cells with a dominant-negative ATF-2 peptide or with small interfering RNA markedly reduced the expression of IFN-gamma and decreased the expression of CREB and c-Jun. These findings suggest that CREB, ATF-2, and c-Jun are recruited to the IFN-gamma proximal promoter and that they up-regulate IFN-gamma transcription in response to microbial Ag. Additionally, ATF-2 controls expression of CREB and c-Jun during T cell activation.

Activating transcription factor

Response element

Chromatin immunoprecipitation

Transcription

10.4049/jimmunol.181.3.2056

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Serum Cytokine Concentrations Do Not ParallelMycobacterium tuberculosis–Induced Cytokine Production in Patients with Tuberculosis

Clinical Infectious Diseases (2003)

Ramakrishna Vankayalapati Benjamin Wizel Stephen E. Weis Peter Klucar Homayoun Shams

We measured serum cytokine concentrations and Mycobacterium tuberculosis–stimulated cytokine production by peripheral blood mononuclear cells (PBMCs) obtained from persons infected with M. tuberculosis. Serum interferon-γ (IFN-γ) and interleukin-10 (IL-10) concentrations were elevated in patients with tuberculosis compared with healthy persons who had reactions to tuberculin skin tests, but IL-18 concentrations were not. In contrast, M. tuberculosis–stimulated PBMCs from patients with tuberculosis produced less IFN-γ and IL-18 but similar amounts of IL-10, compared with PBMCs from healthy subjects who had reactions to tuberculin skin tests. Pretreatment of PBMCs from healthy subjects with reaction to tuberculin with serum from patients with tuberculosis inhibited IFN-γ production in response to M. tuberculosis, and inhibition was blocked by anti–IL-10. Thus, serum concentrations of IFN-γ, IL-18, and IL-10 do not parallel M. tuberculosis–induced cytokine levels, and increased IL-10 serum levels in patients with tuberculosis inhibit IFN-γ production in response to mycobacterial antigens.

10.1086/344903

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Induction and Activation of Human Th17 by Targeting Antigens to Dendritic Cells via Dectin-1

The Journal of Immunology (2014)

Dorothée Duluc HyeMee Joo Ling Ni Wenjie Yin Katherine Upchurch

Recent compelling evidence indicates that Th17 confer host immunity against a variety of microbes, including extracellular and intracellular pathogens. Therefore, understanding mechanisms for the induction and activation of Ag-specific Th17 is important for the rational design of vaccines against pathogens. To study this, we employed an in vitro system in which influenza hemagglutinin (HA) 1 was delivered to dendritic cells (DCs) via Dectin-1 using anti-human Dectin-1 (hDectin-1)-HA1 recombinant fusion proteins. We found that healthy individuals maintained broad ranges of HA1-specific memory Th17 that were efficiently activated by DCs targeted with anti-hDectin-1-HA1. Nonetheless, these DCs were not able to induce a significant level of HA1-specific Th17 responses even in the presence of the Th17-promoting cytokines IL-1β and IL-6. We further found that the induction of surface IL-1R1 expression by signals via TCRs and common γ-chain receptors was essential for naive CD4(+) T cell differentiation into HA1-specific Th17. This process was dependent on MyD88, but not IL-1R-associated kinase 1/4. Thus, interruptions in STAT3 or MyD88 signaling led to substantially diminished HA1-specific Th17 induction. Taken together, the de novo generation of pathogen-specific human Th17 requires complex, but complementary, actions of multiple signals. Data from this study will help us design a new and effective vaccine strategy that can promote Th17-mediated immunity against microbial pathogens.

10.4049/jimmunol.1301661

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Citations (24)

Identification of M-Tuberculosis peptides that are recognized by human CD4+ and CD8+ T-cells from persons expressing different HLA alleles

The FASEB Journal (2003)

Homayoun Shams Peter Klucar Stephen E. Weis Ajit Lalvani H Safi

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Exposure to Cigarette Smoke Inhibits the Pulmonary T-Cell Response to Influenza Virus andMycobacterium tuberculosis

Infection and Immunity (2010)

Yan Feng Ying Kong Peter F. Barnes Fang-Fang Huang Peter Klucar

Smoking is associated with increased susceptibility to tuberculosis and influenza. However, little information is available on the mechanisms underlying this increased susceptibility. Mice were left unexposed or were exposed to cigarette smoke and then infected with Mycobacterium tuberculosis by aerosol or influenza A by intranasal infection. Some mice were given a DNA vaccine encoding an immunogenic M. tuberculosis protein. Gamma interferon (IFN-γ) production by T cells from the lungs and spleens was measured. Cigarette smoke exposure inhibited the lung T-cell production of IFN-γ during stimulation in vitro with anti-CD3, after vaccination with a construct expressing an immunogenic mycobacterial protein, and during infection with M. tuberculosis and influenza A virus in vivo. Reduced IFN-γ production was mediated through the decreased phosphorylation of transcription factors that positively regulate IFN-γ expression. Cigarette smoke exposure increased the bacterial burden in mice infected with M. tuberculosis and increased weight loss and mortality in mice infected with influenza virus. This study provides the first demonstration that cigarette smoke exposure directly inhibits the pulmonary T-cell response to M. tuberculosis and influenza virus in a physiologically relevant animal model, increasing susceptibility to both pathogens.

Tuberculosis vaccines

10.1128/iai.00709-10

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Intradermal vaccination prevents anti-MOG autoimmune encephalomyelitis in macaques

EBioMedicine (2019)

Claire-Maëlle Fovet Lev Stimmer Vanessa Contreras Philippe Horellou Audrey Hubert

BackgroundAutoimmune demyelinating diseases (ADD) are a major cause of neurological disability due to autoreactive cellular and humoral immune responses against brain antigens. A cure for chronic ADD could be obtained by appropriate immunomodulation.MethodsWe implemented a preclinical scheme to foster immune tolerance to myelin oligodendrocyte glycoprotein (MOG), in a cynomolgus-macaque model of experimental autoimmune encephalomyelitis (EAE), in which administration of recombinant human MOG (rhMOG) elicits brain inflammation mediated by MOG-autoreactive CD4+ lymphocytes and anti-MOG IgG. For immunotherapy, we used a recombinant antibody (Ab) directed against the dendritic cell-asialoglycoprotein receptor (DC-ASGPR) fused either to MOG or a control antigen PSA (prostate-specific antigen).FindingsrhMOG and the anti-DC-ASGPR-MOG were respectively detected in CD1a+ DCs or CD163+ cells in the skin of macaques. Intradermal administration of anti-DC-ASGPR-MOG, but not control anti-DC-ASGPR-PSA, was protective against EAE. The treatment prevented the CD4+ T cell activation and proinflammatory cytokine production observed in controls. Moreover, the administration of anti-DC-ASGPR-MOG induced MOG-specific CD4+CD25+FOXP3+CD39+ regulatory lymphocytes and favoured an upsurge in systemic TGFβ and IL-8 upon rhMOG re-administration in vivo.InterpretationWe show that the delivery of an anti-DC-ASGPR-MOG allows antigen-specific adaptive immune modulation to prevent the breach of immune tolerance to MOG. Our findings pave the way for therapeutic vaccines for long-lasting remission to grave encephalomyelitis with identified autoantigens, such as ADD associated with anti-MOG autoantibodies.FundWork supported by the French ANR (ANR-11-INBS-0008 and ANR-10-EQPX-02-01), NIH (NIH 1 R01 AI 105066), the Baylor Scott and White Healthcare System funding and Roche Research Collaborative grants.

Myelin oligodendrocyte glycoprotein

Regulatory T cell

Encephalomyelitis

10.1016/j.ebiom.2019.08.052

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Characterization of a Mycobacterium tuberculosis Peptide That Is Recognized by Human CD4+ and CD8+ T Cells in the Context of Multiple HLA Alleles

The Journal of Immunology (2004)

Homayoun Shams Peter Klucar Steven E. Weis Ajit Lalvani Patrick K. Moonan

The secreted Mycobacterium tuberculosis 10-kDa culture filtrate protein (CFP)10 is a potent T cell Ag that is recognized by a high percentage of persons infected with M. tuberculosis. We determined the molecular basis for this widespread recognition by identifying and characterizing a 15-mer peptide, CFP10(71-85), that elicited IFN-gamma production and CTL activity by both CD4(+) and CD8(+) T cells from persons expressing multiple MHC class II and class I molecules, respectively. CFP10(71-85) contained at least two epitopes, one of 10 aa (peptide T1) and another of 9 aa (peptide T6). T1 was recognized by CD4(+) cells in the context of DRB1*04, DR5*0101, and DQB1*03, and by CD8(+) cells of A2(+) donors. T6 elicited responses by CD4(+) cells in the context of DRB1*04 and DQB1*03, and by CD8(+) cells of B35(+) donors. Deleting a single amino acid from the amino or carboxy terminus of either peptide markedly reduced IFN-gamma production, suggesting that they are minimal epitopes for both CD4(+) and CD8(+) cells. As far as we are aware, these are the shortest microbial peptides that have been found to elicit responses by both T cell subpopulations. The capacity of CFP10(71-85) to stimulate IFN-gamma production and CTL activity by CD4(+) and CD8(+) cells from persons expressing a spectrum of MHC molecules suggests that this peptide is an excellent candidate for inclusion in a subunit antituberculosis vaccine.

CTL*

10.4049/jimmunol.173.3.1966

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Citations (80)