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

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 naive 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.