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Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity.

Shamshiev AT, Ampenberger F, Ernst B, Rohrer L, Marsland BJ, Kopf M - J. Exp. Med. (2007)

Bottom Line: Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses.We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8alpha(-) myeloid DCs and inhibit NF-kappaB nuclear translocation.These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell-mediated immunity.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland.

ABSTRACT
Environmental factors, including diet, play a central role in influencing the balance of normal immune homeostasis; however, many of the cellular mechanisms maintaining this balance remain to be elucidated. Using mouse models of genetic and high-fat/cholesterol diet-induced dyslipidemia, we examined the influence of dyslipidemia on T cell and dendritic cell (DC) responses in vivo and in vitro. We show that dyslipidemia inhibited Toll-like receptor (TLR)-induced production of proinflammatory cytokines, including interleukin (IL)-12, IL-6, and tumor necrosis factor-alpha, as well as up-regulation of costimulatory molecules by CD8alpha(-) DCs, but not by CD8alpha(+) DCs, in vivo. Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses. As a consequence of this immune modulation, host resistance to Leishmania major was compromised. We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8alpha(-) myeloid DCs and inhibit NF-kappaB nuclear translocation. These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell-mediated immunity.

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Dyslipidemia promotes Th2 cell development. (A) Splenic DCs were purified from chow diet– or HFCD-fed C57BL/6 (B6) and apoE−/− mice, followed by co-culture with naive GP61-80-specific CD4+ T cells in the presence of 10 nM GP61-80 peptide. On day 4, the proportion of IL-4– and IFN-γ–producing CD4+ T cells was determined by FACS. Numbers indicate the percentage of cells in each quadrant. (B and C) Naive GP61-80-specific CD4+ T cells (CD45.1+) were CFSE-labeled and transferred i.v. into the indicated mice 1 d before i.p. immunization with 40 μg GP61-80 peptide and 5 nmol CpG. (B) After 3 d, CFSE dilution of adoptively transferred cells was determined by FACS. The frequency of cells within each cycle was calculated after appropriate gating on the CFSE+ populations. (C) After 6 d, the production of IFN-γ and IL-4 by adoptively transferred cells was determined by FACS. Horizontal bars indicate mean values for each group (n = 5–6). Error bars represent the mean ± the SD.
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fig2: Dyslipidemia promotes Th2 cell development. (A) Splenic DCs were purified from chow diet– or HFCD-fed C57BL/6 (B6) and apoE−/− mice, followed by co-culture with naive GP61-80-specific CD4+ T cells in the presence of 10 nM GP61-80 peptide. On day 4, the proportion of IL-4– and IFN-γ–producing CD4+ T cells was determined by FACS. Numbers indicate the percentage of cells in each quadrant. (B and C) Naive GP61-80-specific CD4+ T cells (CD45.1+) were CFSE-labeled and transferred i.v. into the indicated mice 1 d before i.p. immunization with 40 μg GP61-80 peptide and 5 nmol CpG. (B) After 3 d, CFSE dilution of adoptively transferred cells was determined by FACS. The frequency of cells within each cycle was calculated after appropriate gating on the CFSE+ populations. (C) After 6 d, the production of IFN-γ and IL-4 by adoptively transferred cells was determined by FACS. Horizontal bars indicate mean values for each group (n = 5–6). Error bars represent the mean ± the SD.

Mentions: Cytokine production and interactions between T cell and DC costimulatory molecules are key mechanisms by which CD4+ T-cell differentiation is driven toward either the Th1 or Th2 subset. We assessed whether dyslipidemia influenced the capacity of DCs to polarize naive CD4+ T cells. Cocultures comprised of splenic DCs and naive CD4 TCR transgenic (Tg) T cells specific for a lymphocytic choriomeningitis virus glycoprotein-derived Th cell epitope, GP61-80 (20), revealed that DCs isolated from HFCD-fed C57BL/6, and that apoE−/− mice preferentially induced IL-4–producing Th2 cells and reduced the frequency of IFN-γ–producing Th1 cells, as compared with DCs isolated from chow diet–fed C57BL/6 controls (Fig. 2 A). Next, we adoptively transferred CFSE-labeled naive CD4+ T cells from congeneic CD45.1+ TCR-Tg mice (20) into HFCD-fed CD45.2+ apoE−/− or CD45.2+ C57BL/6 mice, and then immunized recipients with GP61-80 peptide together with CpG. After 4 d, at least 8–9 cell divisions were detected in both groups of mice. However, the extent of proliferation was reduced in HFCD-fed apoE−/− mice, as compared with chow diet–fed C57BL/6, chow diet–fed apoE−/−, and HFCD-fed C57BL/6 controls (Fig. 2 B and not depicted), suggesting that CD4 T-cell proliferation was affected by severe dyslipidemia. 6 d after immunization, we restimulated splenocytes with PMA/ionomycin and assessed IL-4 and IFN-γ production by intracellular cytokine staining. The frequency of IFN-γ–producing CD45.1+CD4+ T cells was similar in all four groups of mice, whereas the frequency of IL-4–producing CD45.1+CD4+ T cells was significantly increased in HFCD-fed apoE−/− mice compared with apoE−/− chow diet, C57BL/6 chow diet, and HFCD controls (Fig. 2 C). These data suggest that dyslipidemia alters the Th1/Th2 balance in vitro and in vivo through a DC-mediated mechanism.


Dyslipidemia inhibits Toll-like receptor-induced activation of CD8alpha-negative dendritic cells and protective Th1 type immunity.

Shamshiev AT, Ampenberger F, Ernst B, Rohrer L, Marsland BJ, Kopf M - J. Exp. Med. (2007)

Dyslipidemia promotes Th2 cell development. (A) Splenic DCs were purified from chow diet– or HFCD-fed C57BL/6 (B6) and apoE−/− mice, followed by co-culture with naive GP61-80-specific CD4+ T cells in the presence of 10 nM GP61-80 peptide. On day 4, the proportion of IL-4– and IFN-γ–producing CD4+ T cells was determined by FACS. Numbers indicate the percentage of cells in each quadrant. (B and C) Naive GP61-80-specific CD4+ T cells (CD45.1+) were CFSE-labeled and transferred i.v. into the indicated mice 1 d before i.p. immunization with 40 μg GP61-80 peptide and 5 nmol CpG. (B) After 3 d, CFSE dilution of adoptively transferred cells was determined by FACS. The frequency of cells within each cycle was calculated after appropriate gating on the CFSE+ populations. (C) After 6 d, the production of IFN-γ and IL-4 by adoptively transferred cells was determined by FACS. Horizontal bars indicate mean values for each group (n = 5–6). Error bars represent the mean ± the SD.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2118729&req=5

fig2: Dyslipidemia promotes Th2 cell development. (A) Splenic DCs were purified from chow diet– or HFCD-fed C57BL/6 (B6) and apoE−/− mice, followed by co-culture with naive GP61-80-specific CD4+ T cells in the presence of 10 nM GP61-80 peptide. On day 4, the proportion of IL-4– and IFN-γ–producing CD4+ T cells was determined by FACS. Numbers indicate the percentage of cells in each quadrant. (B and C) Naive GP61-80-specific CD4+ T cells (CD45.1+) were CFSE-labeled and transferred i.v. into the indicated mice 1 d before i.p. immunization with 40 μg GP61-80 peptide and 5 nmol CpG. (B) After 3 d, CFSE dilution of adoptively transferred cells was determined by FACS. The frequency of cells within each cycle was calculated after appropriate gating on the CFSE+ populations. (C) After 6 d, the production of IFN-γ and IL-4 by adoptively transferred cells was determined by FACS. Horizontal bars indicate mean values for each group (n = 5–6). Error bars represent the mean ± the SD.
Mentions: Cytokine production and interactions between T cell and DC costimulatory molecules are key mechanisms by which CD4+ T-cell differentiation is driven toward either the Th1 or Th2 subset. We assessed whether dyslipidemia influenced the capacity of DCs to polarize naive CD4+ T cells. Cocultures comprised of splenic DCs and naive CD4 TCR transgenic (Tg) T cells specific for a lymphocytic choriomeningitis virus glycoprotein-derived Th cell epitope, GP61-80 (20), revealed that DCs isolated from HFCD-fed C57BL/6, and that apoE−/− mice preferentially induced IL-4–producing Th2 cells and reduced the frequency of IFN-γ–producing Th1 cells, as compared with DCs isolated from chow diet–fed C57BL/6 controls (Fig. 2 A). Next, we adoptively transferred CFSE-labeled naive CD4+ T cells from congeneic CD45.1+ TCR-Tg mice (20) into HFCD-fed CD45.2+ apoE−/− or CD45.2+ C57BL/6 mice, and then immunized recipients with GP61-80 peptide together with CpG. After 4 d, at least 8–9 cell divisions were detected in both groups of mice. However, the extent of proliferation was reduced in HFCD-fed apoE−/− mice, as compared with chow diet–fed C57BL/6, chow diet–fed apoE−/−, and HFCD-fed C57BL/6 controls (Fig. 2 B and not depicted), suggesting that CD4 T-cell proliferation was affected by severe dyslipidemia. 6 d after immunization, we restimulated splenocytes with PMA/ionomycin and assessed IL-4 and IFN-γ production by intracellular cytokine staining. The frequency of IFN-γ–producing CD45.1+CD4+ T cells was similar in all four groups of mice, whereas the frequency of IL-4–producing CD45.1+CD4+ T cells was significantly increased in HFCD-fed apoE−/− mice compared with apoE−/− chow diet, C57BL/6 chow diet, and HFCD controls (Fig. 2 C). These data suggest that dyslipidemia alters the Th1/Th2 balance in vitro and in vivo through a DC-mediated mechanism.

Bottom Line: Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses.We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8alpha(-) myeloid DCs and inhibit NF-kappaB nuclear translocation.These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell-mediated immunity.

View Article: PubMed Central - PubMed

Affiliation: Molecular Biomedicine, Institute of Integrative Biology, Swiss Federal Institute of Technology Zürich, 8952 Zürich, Switzerland.

ABSTRACT
Environmental factors, including diet, play a central role in influencing the balance of normal immune homeostasis; however, many of the cellular mechanisms maintaining this balance remain to be elucidated. Using mouse models of genetic and high-fat/cholesterol diet-induced dyslipidemia, we examined the influence of dyslipidemia on T cell and dendritic cell (DC) responses in vivo and in vitro. We show that dyslipidemia inhibited Toll-like receptor (TLR)-induced production of proinflammatory cytokines, including interleukin (IL)-12, IL-6, and tumor necrosis factor-alpha, as well as up-regulation of costimulatory molecules by CD8alpha(-) DCs, but not by CD8alpha(+) DCs, in vivo. Decreased DC activation profoundly influenced T helper (Th) cell responses, leading to impaired Th1 and enhanced Th2 responses. As a consequence of this immune modulation, host resistance to Leishmania major was compromised. We found that oxidized low-density lipoprotein (oxLDL) was the key active component responsible for this effect, as it could directly uncouple TLR-mediated signaling on CD8alpha(-) myeloid DCs and inhibit NF-kappaB nuclear translocation. These results show that a dyslipidemic microenvironment can directly interfere with DC responses to pathogen-derived signals and skew the development of T cell-mediated immunity.

Show MeSH
Related in: MedlinePlus