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Up-regulated S100 calcium binding protein A8 in Plasmodium-infected patients correlates with CD4(+)CD25(+)Foxp3 regulatory T cell generation.

Lee HW, Kim TS, Kang YJ, Kim JY, Lee S, Lee WJ, Sohn Y - Malar. J. (2015)

Bottom Line: A higher amount of S100A8 was detected in vivax-infected patients (141.2 ± 61.849 ng/ml, n = 40) compared with normal control group (48.1 ± 27.384 ng/ml, n = 40).The level of S100A8 did not coincide with that of anti-malarial antibody measured by indirect fluorescent antibody test (IFAT) using parasite-infected red blood cells as antigen.However, the serum levels of S100A8 decreased with increase in parasitaemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA. rainlee67@naver.com.

ABSTRACT

Background: The pro-inflammatory S100 calcium binding protein A8 (S100A8) is elevated in the serum of patients with Plasmodium falciparum malaria, but its function in Plasmodium vivax malaria is not yet clear. This function was investigated in P. vivax-infected patients in this study.

Methods: The level of S100A8 in the serum was measured with ELISA. Full amino acids of S100A8 were synthesized to verify the functions for maturation of immature dendritic cell (iDC) and evaluation of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) generation by mature DC (mDC).

Results: A higher amount of S100A8 was detected in vivax-infected patients (141.2 ± 61.849 ng/ml, n = 40) compared with normal control group (48.1 ± 27.384 ng/ml, n = 40). The level of S100A8 did not coincide with that of anti-malarial antibody measured by indirect fluorescent antibody test (IFAT) using parasite-infected red blood cells as antigen. Programmed death-ligand 1 (PD-L1) was up-regulated on the surface of iDCs following treatment with synthetic S100A8, not with synthetic MSP-1, AMA-1 and CSP, as compared to the expression seen for non-treated iDCs. The addition of red blood cells of infected patients to iDCs also elevated their surface expression of CD86. However, the serum levels of S100A8 decreased with increase in parasitaemia. DCs matured by sera containing S100A8 generated Treg cells from naïve T cells. The ratio of Treg cells generated was inversely proportional to the concentration of S100A8 in sera.

Conclusions: Treg cells suppress the activity of cytotoxic T cells, which kill malaria parasites; therefore, the up-regulation of S100A8 in malaria patients may contribute to pathogen immune escape or tolerance.

No MeSH data available.


Related in: MedlinePlus

CD4+CD25+Foxp3+ regulatory T (Treg) cell generation by synthetic S100A8. Naïve T cells (CD4+CD25−Foxp3−) were isolated from the peripheral blood of healthy volunteers and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies in the presence of 100 U/ml recombinant interleukin-2 (rIL-2) and/or synthetic peptides for 5 days. To monitor the cell proliferation, naïve T cells were stained with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE). Treg cell generation was evaluated by FACS analysis. a A representative result of FACS profile of Treg generation by LPS and sS100A8. b Significantly increased Treg generation by LPS and sS100A8 obtained by seven separate experiments with different volunteers’ DC each. Significant differences were determined using the one-way ANOVA (*P < 0.05, **P < 0.01, n = 5)
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Fig7: CD4+CD25+Foxp3+ regulatory T (Treg) cell generation by synthetic S100A8. Naïve T cells (CD4+CD25−Foxp3−) were isolated from the peripheral blood of healthy volunteers and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies in the presence of 100 U/ml recombinant interleukin-2 (rIL-2) and/or synthetic peptides for 5 days. To monitor the cell proliferation, naïve T cells were stained with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE). Treg cell generation was evaluated by FACS analysis. a A representative result of FACS profile of Treg generation by LPS and sS100A8. b Significantly increased Treg generation by LPS and sS100A8 obtained by seven separate experiments with different volunteers’ DC each. Significant differences were determined using the one-way ANOVA (*P < 0.05, **P < 0.01, n = 5)

Mentions: The combined blockade of PD-L1 and lymphocyte-activation gene 3 (LAG-3) accelerates the clearance of yoelii malaria and correlates with improved CD4+ T cell and B cell responses [26]. However, since PD-L1 can interact specifically with both B7-1 [27] and PD-1 [28] to inhibit T cell activation, either pathway—individually or cooperatively—could contribute to the attrition of malarial immunity. Therefore, further analysis of the functional status of matured DCs in healthy volunteers was examined by measuring their capability to induce Treg cells. Significantly, the presence of LPS (67.4 %) and S100A8 (65.2 %) induced Treg cells as much as two times higher than non-treated control cells (24.8 %, Fig. 7a). When Treg generation was tested with seven volunteers’ DC, control group showed Treg generation as 18 ± 14.13 % and sS100A8-treated group (29.40 ± 14.90 %) showed higher than LPS-treated group (27.93 ± 16.70 %) (Fig. 7b). Furthermore, naïve T cells cultured with S100A8-containing sera led to Treg cell generation that was inversely proportional to the concentration of S100A8 in the sera (Fig. 8, P = 0.0245, n = 10). Interestingly, synthetic S100A8 always increased the induction of Treg cells in PBMCs isolated from healthy volunteers (Fig. 9d, P = 0.0465), but was not constant in synthetic MSP-1, AMA-1 and CSP treatments (Fig. 9a–c).Fig. 7


Up-regulated S100 calcium binding protein A8 in Plasmodium-infected patients correlates with CD4(+)CD25(+)Foxp3 regulatory T cell generation.

Lee HW, Kim TS, Kang YJ, Kim JY, Lee S, Lee WJ, Sohn Y - Malar. J. (2015)

CD4+CD25+Foxp3+ regulatory T (Treg) cell generation by synthetic S100A8. Naïve T cells (CD4+CD25−Foxp3−) were isolated from the peripheral blood of healthy volunteers and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies in the presence of 100 U/ml recombinant interleukin-2 (rIL-2) and/or synthetic peptides for 5 days. To monitor the cell proliferation, naïve T cells were stained with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE). Treg cell generation was evaluated by FACS analysis. a A representative result of FACS profile of Treg generation by LPS and sS100A8. b Significantly increased Treg generation by LPS and sS100A8 obtained by seven separate experiments with different volunteers’ DC each. Significant differences were determined using the one-way ANOVA (*P < 0.05, **P < 0.01, n = 5)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4594961&req=5

Fig7: CD4+CD25+Foxp3+ regulatory T (Treg) cell generation by synthetic S100A8. Naïve T cells (CD4+CD25−Foxp3−) were isolated from the peripheral blood of healthy volunteers and stimulated with anti-CD3 and anti-CD28 monoclonal antibodies in the presence of 100 U/ml recombinant interleukin-2 (rIL-2) and/or synthetic peptides for 5 days. To monitor the cell proliferation, naïve T cells were stained with the fluorescent dye carboxyfluorescein succinimidyl ester (CFSE). Treg cell generation was evaluated by FACS analysis. a A representative result of FACS profile of Treg generation by LPS and sS100A8. b Significantly increased Treg generation by LPS and sS100A8 obtained by seven separate experiments with different volunteers’ DC each. Significant differences were determined using the one-way ANOVA (*P < 0.05, **P < 0.01, n = 5)
Mentions: The combined blockade of PD-L1 and lymphocyte-activation gene 3 (LAG-3) accelerates the clearance of yoelii malaria and correlates with improved CD4+ T cell and B cell responses [26]. However, since PD-L1 can interact specifically with both B7-1 [27] and PD-1 [28] to inhibit T cell activation, either pathway—individually or cooperatively—could contribute to the attrition of malarial immunity. Therefore, further analysis of the functional status of matured DCs in healthy volunteers was examined by measuring their capability to induce Treg cells. Significantly, the presence of LPS (67.4 %) and S100A8 (65.2 %) induced Treg cells as much as two times higher than non-treated control cells (24.8 %, Fig. 7a). When Treg generation was tested with seven volunteers’ DC, control group showed Treg generation as 18 ± 14.13 % and sS100A8-treated group (29.40 ± 14.90 %) showed higher than LPS-treated group (27.93 ± 16.70 %) (Fig. 7b). Furthermore, naïve T cells cultured with S100A8-containing sera led to Treg cell generation that was inversely proportional to the concentration of S100A8 in the sera (Fig. 8, P = 0.0245, n = 10). Interestingly, synthetic S100A8 always increased the induction of Treg cells in PBMCs isolated from healthy volunteers (Fig. 9d, P = 0.0465), but was not constant in synthetic MSP-1, AMA-1 and CSP treatments (Fig. 9a–c).Fig. 7

Bottom Line: A higher amount of S100A8 was detected in vivax-infected patients (141.2 ± 61.849 ng/ml, n = 40) compared with normal control group (48.1 ± 27.384 ng/ml, n = 40).The level of S100A8 did not coincide with that of anti-malarial antibody measured by indirect fluorescent antibody test (IFAT) using parasite-infected red blood cells as antigen.However, the serum levels of S100A8 decreased with increase in parasitaemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, 32610, USA. rainlee67@naver.com.

ABSTRACT

Background: The pro-inflammatory S100 calcium binding protein A8 (S100A8) is elevated in the serum of patients with Plasmodium falciparum malaria, but its function in Plasmodium vivax malaria is not yet clear. This function was investigated in P. vivax-infected patients in this study.

Methods: The level of S100A8 in the serum was measured with ELISA. Full amino acids of S100A8 were synthesized to verify the functions for maturation of immature dendritic cell (iDC) and evaluation of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) generation by mature DC (mDC).

Results: A higher amount of S100A8 was detected in vivax-infected patients (141.2 ± 61.849 ng/ml, n = 40) compared with normal control group (48.1 ± 27.384 ng/ml, n = 40). The level of S100A8 did not coincide with that of anti-malarial antibody measured by indirect fluorescent antibody test (IFAT) using parasite-infected red blood cells as antigen. Programmed death-ligand 1 (PD-L1) was up-regulated on the surface of iDCs following treatment with synthetic S100A8, not with synthetic MSP-1, AMA-1 and CSP, as compared to the expression seen for non-treated iDCs. The addition of red blood cells of infected patients to iDCs also elevated their surface expression of CD86. However, the serum levels of S100A8 decreased with increase in parasitaemia. DCs matured by sera containing S100A8 generated Treg cells from naïve T cells. The ratio of Treg cells generated was inversely proportional to the concentration of S100A8 in sera.

Conclusions: Treg cells suppress the activity of cytotoxic T cells, which kill malaria parasites; therefore, the up-regulation of S100A8 in malaria patients may contribute to pathogen immune escape or tolerance.

No MeSH data available.


Related in: MedlinePlus