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In vivo microRNA-155 expression influences antigen-specific T cell-mediated immune responses generated by DNA vaccination.

Mao CP, He L, Tsai YC, Peng S, Kang TH, Pang X, Monie A, Hung CF, Wu TC - Cell Biosci (2011)

Bottom Line: Biolistic epidermal transfection with DNA encoding miR-155 suppressed the induction of antigen-specific T cell-mediated immunity, whereas reduction of endogenous miR-155 by a partially complementary antisense sequence reversed this effect.Because DCs represent a significant component of epidermal tissue and are among the most potent of antigen-presenting cells, the inhibitory actions of miR-155 could be mediated through this subset of cells.These results suggest that miR-155 may repress the expression of key molecules involved in lymph node migration, antigen presentation, or T cell activation in DCs, and thus forms part of a negative regulatory pathway that dampens the generation of T cell-mediated immune responses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. wutc@jhmi.edu.

ABSTRACT

Background: MicroRNA (miRNA) molecules are potent mediators of post-transcriptional gene silencing that are emerging to be critical in the regulation of innate and adaptive immunity.

Results: Here we report that miR-155--an oncogenic miRNA with important function in the mammalian immune system--is induced in dendritic cells (DCs) upon maturation and potentially attenuates their ability to activate T cells. Biolistic epidermal transfection with DNA encoding miR-155 suppressed the induction of antigen-specific T cell-mediated immunity, whereas reduction of endogenous miR-155 by a partially complementary antisense sequence reversed this effect. Because DCs represent a significant component of epidermal tissue and are among the most potent of antigen-presenting cells, the inhibitory actions of miR-155 could be mediated through this subset of cells.

Conclusions: These results suggest that miR-155 may repress the expression of key molecules involved in lymph node migration, antigen presentation, or T cell activation in DCs, and thus forms part of a negative regulatory pathway that dampens the generation of T cell-mediated immune responses. Modulation of miR-155 expression in epidermis therefore represents a potentially promising form of gene therapy for the control of diseases ranging from autoimmunity to cancer and viral infection.

No MeSH data available.


Related in: MedlinePlus

Characterization of the number of E7-specific IFN-γ CD8+ T cells in mice vaccinated intradermally with CRT/E7 DNA in combination with either bic155 or a control construct. A, C57BL/6 mice (3 per group) were immunized with CRT/E7 DNA in combination with either bic155 (left panels) or a control construct (right panels). At day 7, animals received boosters at the same dose and regimen. At day 14, splenocytes were harvested, cultured for 15 hrs with (top panels) or without (bottom panels) E7 peptide, and stained for surface CD8 and intracellular IFN-γ. Cells were analyzed by flow cytometry. The top right quadrant in each dot plot indicates the number of IFN-γ-secreting E7-specific CD8+ T cells. B, Bar graph representation of the flow cytometry data (mean ± SD).
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Figure 3: Characterization of the number of E7-specific IFN-γ CD8+ T cells in mice vaccinated intradermally with CRT/E7 DNA in combination with either bic155 or a control construct. A, C57BL/6 mice (3 per group) were immunized with CRT/E7 DNA in combination with either bic155 (left panels) or a control construct (right panels). At day 7, animals received boosters at the same dose and regimen. At day 14, splenocytes were harvested, cultured for 15 hrs with (top panels) or without (bottom panels) E7 peptide, and stained for surface CD8 and intracellular IFN-γ. Cells were analyzed by flow cytometry. The top right quadrant in each dot plot indicates the number of IFN-γ-secreting E7-specific CD8+ T cells. B, Bar graph representation of the flow cytometry data (mean ± SD).

Mentions: C57BL/6 mice were intradermally administered with CRT/E7 in combination with either bic155 or a control construct. Animals were boosted with the same dose and regimen on day 7. Splenocytes were harvested on day 14 and cultured for 15 hrs in the presence or absence of E7 peptide. Cells were then costained for intracellular IFN-γ and surface CD8 and subsequently analyzed by flow cytometry. As demonstrated in Figure 3A, coadministration with bic155, compared to control, greatly decreased the number of IFN-γ-secreting, E7-specific CD8+ T cells induced by CRT/E7. As expected, splenocytes in both vaccination groups not pulsed with E7 peptide contained negligible numbers of IFN-γ-secreting, E7-specific CD8+ T cells. Figure 3B is a bar graph representation of the data (* p < 0.005). Our data suggest that miR-155 mediates an important immunosuppressive function in DCs, perhaps through the post-transcriptional knockdown of molecules that are central to T cell activation.


In vivo microRNA-155 expression influences antigen-specific T cell-mediated immune responses generated by DNA vaccination.

Mao CP, He L, Tsai YC, Peng S, Kang TH, Pang X, Monie A, Hung CF, Wu TC - Cell Biosci (2011)

Characterization of the number of E7-specific IFN-γ CD8+ T cells in mice vaccinated intradermally with CRT/E7 DNA in combination with either bic155 or a control construct. A, C57BL/6 mice (3 per group) were immunized with CRT/E7 DNA in combination with either bic155 (left panels) or a control construct (right panels). At day 7, animals received boosters at the same dose and regimen. At day 14, splenocytes were harvested, cultured for 15 hrs with (top panels) or without (bottom panels) E7 peptide, and stained for surface CD8 and intracellular IFN-γ. Cells were analyzed by flow cytometry. The top right quadrant in each dot plot indicates the number of IFN-γ-secreting E7-specific CD8+ T cells. B, Bar graph representation of the flow cytometry data (mean ± SD).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3116247&req=5

Figure 3: Characterization of the number of E7-specific IFN-γ CD8+ T cells in mice vaccinated intradermally with CRT/E7 DNA in combination with either bic155 or a control construct. A, C57BL/6 mice (3 per group) were immunized with CRT/E7 DNA in combination with either bic155 (left panels) or a control construct (right panels). At day 7, animals received boosters at the same dose and regimen. At day 14, splenocytes were harvested, cultured for 15 hrs with (top panels) or without (bottom panels) E7 peptide, and stained for surface CD8 and intracellular IFN-γ. Cells were analyzed by flow cytometry. The top right quadrant in each dot plot indicates the number of IFN-γ-secreting E7-specific CD8+ T cells. B, Bar graph representation of the flow cytometry data (mean ± SD).
Mentions: C57BL/6 mice were intradermally administered with CRT/E7 in combination with either bic155 or a control construct. Animals were boosted with the same dose and regimen on day 7. Splenocytes were harvested on day 14 and cultured for 15 hrs in the presence or absence of E7 peptide. Cells were then costained for intracellular IFN-γ and surface CD8 and subsequently analyzed by flow cytometry. As demonstrated in Figure 3A, coadministration with bic155, compared to control, greatly decreased the number of IFN-γ-secreting, E7-specific CD8+ T cells induced by CRT/E7. As expected, splenocytes in both vaccination groups not pulsed with E7 peptide contained negligible numbers of IFN-γ-secreting, E7-specific CD8+ T cells. Figure 3B is a bar graph representation of the data (* p < 0.005). Our data suggest that miR-155 mediates an important immunosuppressive function in DCs, perhaps through the post-transcriptional knockdown of molecules that are central to T cell activation.

Bottom Line: Biolistic epidermal transfection with DNA encoding miR-155 suppressed the induction of antigen-specific T cell-mediated immunity, whereas reduction of endogenous miR-155 by a partially complementary antisense sequence reversed this effect.Because DCs represent a significant component of epidermal tissue and are among the most potent of antigen-presenting cells, the inhibitory actions of miR-155 could be mediated through this subset of cells.These results suggest that miR-155 may repress the expression of key molecules involved in lymph node migration, antigen presentation, or T cell activation in DCs, and thus forms part of a negative regulatory pathway that dampens the generation of T cell-mediated immune responses.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. wutc@jhmi.edu.

ABSTRACT

Background: MicroRNA (miRNA) molecules are potent mediators of post-transcriptional gene silencing that are emerging to be critical in the regulation of innate and adaptive immunity.

Results: Here we report that miR-155--an oncogenic miRNA with important function in the mammalian immune system--is induced in dendritic cells (DCs) upon maturation and potentially attenuates their ability to activate T cells. Biolistic epidermal transfection with DNA encoding miR-155 suppressed the induction of antigen-specific T cell-mediated immunity, whereas reduction of endogenous miR-155 by a partially complementary antisense sequence reversed this effect. Because DCs represent a significant component of epidermal tissue and are among the most potent of antigen-presenting cells, the inhibitory actions of miR-155 could be mediated through this subset of cells.

Conclusions: These results suggest that miR-155 may repress the expression of key molecules involved in lymph node migration, antigen presentation, or T cell activation in DCs, and thus forms part of a negative regulatory pathway that dampens the generation of T cell-mediated immune responses. Modulation of miR-155 expression in epidermis therefore represents a potentially promising form of gene therapy for the control of diseases ranging from autoimmunity to cancer and viral infection.

No MeSH data available.


Related in: MedlinePlus