Functional skewing of bone marrow-derived dendritic cells by Th1- or Th2-inducing cytokines

Sato, Masamitsu; Iwakabe, Kenji; Kimura, Shuichi; Nishimura, Takashi

doi:10.1016/s0165-2478(98)00186-2

Cited by 47 publications

(45 citation statements)

References 25 publications

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“…36,38 This view is also supported by a recent study by Mosca et al, 39 which suggests that Flt-3L expanded DC can only stimulate allogeneic T cells to secrete g-IFN after having been exposed to additional maturation signals. In conclusion, we feel that the use of Flt-3L alone cannot be recommended for immunological antitumor therapy, but the use of other cytokines and/or immunomodulatory molecules together with Flt-3L might offer attractive perspectives for immunotherapy.…”

Section: Discussionmentioning

confidence: 72%

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

et al. 2004

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Since transfection of dendritic cells (DC) plays a key role in DNA vaccination, in vivo expansion of DC might be a tool to increase vaccine efficacy. We asked whether Fms-like tyrosine kinase-3 ligand (Flt-3L), a growth factor for DC, can be used as an adjuvant for DNA vaccination. Betagalactosidase (b-gal) was used as a model antigen in C57BL/6 mice. Mice were immunized i.m. with DNA coding for b-gal with or without additional injection of Flt-3L. In both cases, antigen-specific CD4 þ and CD8 þ T cells were detectable after vaccination. Compared with DNA alone, additional administration of Flt-3L led to a significant increase in the antigen-specific proliferative response. However, increased cytotoxicity by T cells was not observed. The cytokines secreted by splenocytes of immunized mice upon in vitro stimulation with antigen had a TH2 profile. Humoral responses against b-gal preferentially consisted of IgG1 antibodies. Analysis of DC from Flt-3L-treated mice revealed an immature phenotype with low or absent expression levels of CD80, CD86 and CD40. We conclude that Flt-3L does not generally skew immune responses towards a TH1 type. More likely, factors determined by the antigen and/or the vaccination procedure itself are crucial for the resulting type of immune response. Flt-3L -under circumstances such as the one we have investigated -can also lead to suppression of TH1 T cell immunity, possibly by expansion of immature/ unactivated DC.

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Section: Discussionmentioning

confidence: 72%

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

et al. 2004

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“…As this experiment has not yet been done, it is not possible to exclude a direct costimulatory role for MD-1 on T cells. In addition, it is important to note that we have not investigated other functional properties of these ODN-treated, LPS-stimulated, DC, including, for instance, production of IL-12, which has itself been implicated in the regulation of type 1 cytokine production (20).…”

Section: Discussionmentioning

confidence: 99%

“…The fulllength sequence for one of these (clone 71 in Ref. 15) was recently identified as the murine homologue of chicken MD-1 (20). MD-1 has been reported to regulate expression of RP105 on B cells (21).…”

mentioning

confidence: 99%

Regulation of Gene Expression of Murine MD-1 Regulates Subsequent T Cell Activation and Cytokine Production

Gorczynski

Chen

Clark

et al. 2000

The Journal of Immunology

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The immunoadhesin (OX2:Fc) comprising the extracellular domain of murine OX2 linked to IgG2aFc, inhibits production of IL-2 and IFN-γ by activated T cells and increases allograft and xenograft survival in vivo. Increased expression of OX2 on dendritic cells (DC) in vivo following preimmunization via the portal vein is also associated with elevated expression of MD-1. We have used antisense oligodeoxynucleotides (ODNs) to MD-1 to investigate the effect of inhibition of expression of MD-1 by DC on their function as allostimulatory cells. We also investigated by FACS analysis the cell surface expression of OX2, CD80, and CD86 on DC incubated with ODN-1 blocking MD-1 expression. Blocking MD-1 gene expression inhibits surface expression of CD80 and CD86, but not of OX2. DC incubated with ODN-1 to MD-1 did not stimulate IL-2 or IFN-γ production, but generated cells able to suppress, in a second culture of fresh DC plus allogeneic T cells, production of IL-2 and IFN-γ. This inhibition was blocked by anti-OX2 mAb. Infusion of DC preincubated with ODN-1 prolonged renal allograft survival, an effect also reversed by anti-OX2 mAb. By FACS, incubation of DC with anti-MD-1 Ab to promote capping eliminated cell surface expression of MD-1 and CD14 without altering DEC205, DC26, CD80, CD86, or OX2 expression. Thus OX2 and MD-1 are independent surface molecules on DC that may reciprocally regulate T cell stimulation. MD-1 is linked to CD14, a “danger receptor complex,” and activation of this complex can regulate cell surface expression of CD80/CD86, which signal T cells.

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“…DCs that induce a Th1 response can therefore be valuable for cancer immunotherapy. DCs that secrete Th1-driving cytokines have been referred to as type-1 polarized dendritic cells, or DC1 (9,10). Conversely, DC2s, which produce a lower level of IL-12, induce the polarization of Th cells toward a Th2 phenotype.…”

Section: Endritic Cells (Dcs)mentioning

confidence: 99%

AIMP1/p43 Protein Induces the Maturation of Bone Marrow-Derived Dendritic Cells with T Helper Type 1-Polarizing Ability

Kim

et al. 2008

The Journal of Immunology

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AIMP1 (ARS-interacting multifunctional protein 1), previously known as p43, was initially identified as a factor associated with a macromolecular tRNA synthetase complex. Recently, we demonstrated that AIMP1 is also secreted and acts as a novel pleiotropic cytokine. In this study, we investigated whether AIMP1 induces the activation and maturation of murine bone marrow-derived dendritic cells (DCs). AIMP1-treated DCs exhibited up-regulated expression of cell-surface molecules, including CD40, CD86, and MHC class II. Additionally, microarray analysis and RT-PCR determinations indicated that the expression of known DC maturation genes also increased significantly following treatment with AIMP1. Treatment of DCs with AIMP1 resulted in a significant increase in IL-12 production and Ag-presenting capability, and it also stimulated the proliferation of allogeneic T cells. Importantly, AIMP1-treated DCs induced activation of Ag-specific Th type 1 (Th1) cells in vitro and in vivo. AIMP1-stimulated DCs significantly enhanced the IFN-γ production of cocultured CD4+ T cells. Immunization of mice with keyhole limpet hemocyanin-pulsed AIMP1 DCs efficiently led to Ag-specific Th1 cell responses, as determined by flow cytometry and ELISA. The addition of a neutralizing anti-IL-12 mAb to the cell cultures that had been treated with AIMP1 resulted in the decreased production of IFN-γ, thereby indicating that AIMP1-stimulated DCs may enhance the Th1 response through increased production of IL-12 by APCs. Taken together, these results indicate that AIMP1 protein induces the maturation and activation of DCs, which skew the immune response toward a Th1 response.

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Functional skewing of bone marrow-derived dendritic cells by Th1- or Th2-inducing cytokines

Cited by 47 publications

References 25 publications

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

Regulation of Gene Expression of Murine MD-1 Regulates Subsequent T Cell Activation and Cytokine Production

AIMP1/p43 Protein Induces the Maturation of Bone Marrow-Derived Dendritic Cells with T Helper Type 1-Polarizing Ability

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