Cell-surface bound pertussis toxin induces polyclonal T cell responses with high levels of interferon-γ in the absence of interleukin-12

Accessory cell surface molecules, such as T cell antigen CD2 and its ligand lymphocyte function-associated antigen 3 (LFA-3; CD58), are critical costimulatory pathways for optimal T cell activation in response to antigens. Interaction of CD2 with cell surface LFA-3 not only increases T cell/accessory cell adhesion, but also induces signal transduction events involved in the regulation of T cell responses. In this report, we show that specific interactions of LFA-3 with CD2 can result in T cell unresponsiveness to antigenic or mitogenic stimuli in vitro. By deletion of certain regions of the extracellular domain of LFA-3, we localized the CD2 binding site to the first domain of LFA-3. We then demonstrated that a soluble, purified first domain-LFA-3/IgG1 fusion protein (LFA3TIP) interacts with CD2 and binds to the same CD2 epitope as purified multimeric or cell surface-expressed LFA-3. LFA3TIP inhibits tetanus toxoid, hepatitis B surface antigen, anti-CD3 mAb, Con A, and phytohemagglutinin P-induced T cell proliferation, as well as xenogeneic and allogeneic mixed lymphocyte reactions (MLR). Unlike anti-LFA-3 or anti-CD2 monoclonal antibodies (mAbs) which inhibit T cell responses by blocking LFA-3/CD2 binding, LFA3TIP is capable of rendering T cells unresponsive to antigenic stimuli in situations where T cell activation is independent of CD2/LFA-3 interactions. Furthermore, LFA3TIP, but not blocking anti-CD2 mAbs, is capable of inducing T cell unresponsiveness to secondary stimulation in allogeneic MLR. This inhibition of T cell responses by LFA3TIP occurs through a different mechanism from that of mAbs to LFA-3 or CD2.

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T-Cell Immune Response Assessment as a Complement to Serology and Intranasal Protection Assays in Determining the Protective Immunity Induced by Acellular Pertussis Vaccines in Mice

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.10.4.637-642.2003 ◽

2003 ◽

Vol 10 (4) ◽

pp. 637-642 ◽

Cited By ~ 3

Author(s):

C. M. Ausiello ◽

R. Lande ◽

P. Stefanelli ◽

C. Fazio ◽

G. Fedele ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Pertussis Toxin ◽

Protective Immunity ◽

T Cell Responses ◽

Additional Tool ◽

Cell Responses ◽

T Cell Immune Responses ◽

Ifn Γ

ABSTRACT The relative value of antibodies and/or T-cell immune responses to Bordetella pertussis antigens in the immunity induced by acellular pertussis (aP) vaccines is still an open issue, probably due to the incomplete knowledge on the mechanisms of protective immunity to pertussis. The relevance of T-cell immune responses in protection from pertussis has been demonstrated in murine and human models of infection; thus, in this study, the ability of different vaccine preparations of three component (pertussis toxin, filamentous hemagglutinin, and pertactin) aP vaccines to induce T-cell responses was investigated in mice. All vaccine preparations examined passed the immunogenicity control test, based on antibody titer assessment, according to European Pharmacopoeia standards, and protected mice from B. pertussis intranasal challenge, but not all preparations were able to prime T cells to pertussis toxin, the specific B. pertussis antigen. In particular, one vaccine preparation was unable to induce proliferation and gamma interferon (IFN-γ) production while the other two gave borderline results. The evaluation of T-cell responses to pertussis toxin antigen may provide information on the protective immunity induced by aP vaccines in animal models. Considering the critical role of the axis interleukin-12-IFN-γ for protection from pertussis, our results suggest that testing the induction of a key protective cytokine such as IFN-γ could be an additional tool for the evaluation of the immune response induced by aP vaccines.

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Development and dynamics of robust T-cell responses to CML under imatinib treatment

Blood ◽

10.1182/blood-2007-12-128397 ◽

2008 ◽

Vol 111 (11) ◽

pp. 5342-5349 ◽

Cited By ~ 57

Author(s):

Christiane I-U. Chen ◽

Holden T. Maecker ◽

Peter P. Lee

Keyword(s):

T Cell ◽

T Cell Responses ◽

Interferon Γ ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Imatinib Treatment ◽

Cell Responses ◽

Major Response ◽

Dividing Cells ◽

Factor Α

Abstract Novel molecular targeted therapies, such as imatinib for chronic myelogenous leukemia (CML), represent the first agents that inhibit cancer cells more than other dividing cells, such as immune cells. We hypothesize that imatinib may create a window in which the immune response is partially restored while apoptotic leukemic cells are present, thus rendering leukemic cells immunogenic as patients enter remission. To detect and quantify antileukemia immune responses in an antigen-unbiased way, we used cryopreserved autologous pretreatment blood samples (representing predominantly leukemic cells) as stimulators to detect antileukemia T-cell responses in CML patients in remission on imatinib. We studied patients over time to address the dynamics of such responses. Our data show that antileukemia T-cell responses develop in the majority of CML patients (9 of 14) in remission and that CD4+ T cells producing tumor necrosis factor-α (median 17.6%) represent the major response over interferon-γ. This confirms the immune system's ability to respond to leukemia under certain conditions. Such responses may be further amplified as a potential therapy that synergizes with imatinib for improved control of CML.

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Mature dendritic cells pulsed with freeze–thaw cell lysates define an effective in vitro vaccine designed to elicit EBV-specific CD4+ and CD8+ T lymphocyte responses

Blood ◽

10.1182/blood.v96.5.1857 ◽

2000 ◽

Vol 96 (5) ◽

pp. 1857-1864 ◽

Cited By ~ 91

Author(s):

Wolfgang Herr ◽

Elena Ranieri ◽

Walter Olson ◽

Hassane Zarour ◽

Loreto Gesualdo ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Mhc Class I ◽

T Cell Responses ◽

Class Ii ◽

Interferon Γ ◽

Class I ◽

Freeze Thaw ◽

Cell Responses

Abstract Immunotherapy trials targeting the induction of tumor-reactive T-cell responses in cancer patients appear to hold significant promise. Because nonmutated lineage-specific antigens and mutated idiotypic antigens may be coexpressed by tumor cells, the use of autologous tumor material to promote the broadest range of antitumor T-cell specificities has significant clinical potential in cancer vaccination trials. As a model for vaccination in the cancer setting, we chose to analyze the promotion of T-cell responses against Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cell line (B-LCL)–derived antigens in vitro. A series of bulk antigenic formats (freeze–thaw lysate, trifluoroacetic acid lysate, extracted membranes, affinity-purified MHC class I– and class II–presented peptides, acid-eluted peptides) prepared from EBV B-LCLs were tested for their ability to stimulate EBV B-LCL–reactive CD4+ and CD8+ T lymphocytes in vitro when pulsed onto autologous dendritic cells (DCs). DC presentation of freeze–thaw lysate material derived from (either autologous or allogeneic) EBV B-LCLs with an Mr of 10 kd or larger stimulated optimal anti-EBV B-LCL responsiveness from freshly isolated CD4+ and CD8+ peripheral blood T cells. These in vivo “memory” T-cell responses were observed only in EBV-seropositive donors. CD4+ T-cell responses to lysate-pulsed DCs were Th1 type (ie, strong interferon-γ and weak interleukin-5 responses). While CD8+ T-cell responses were also observed in interferon-γ Elispot assays and in cytotoxicity assays, these responses were of low frequency unless the DC stimulators were induced to “mature” after being fed with tumor lysates. Optimal-length, naturally processed, and MHC class I– or class II–presented tumor peptides were comparatively poorly immunogenic in this model system.

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