Modulation of dendritic cell function and immune response by cysteine protease inhibitor from murine nematode...

Modulation and suppression of the immune response of the host by nematode parasites have been reported extensively and the cysteine protease inhibitor (CPI or cystatin) is identified as one of the major immunomodulators. In the present study, we cloned and produced recombinant CPI protein from the murine nematode parasite Heligmosomoides polygyrus (rHp-CPI) and investigated its immunomodulatory effects on dendritic cell (DC) function and immune responses in mice. Bone-marrow-derived CD11c(+) DC (BMDC) that were exposed to rHp-CPI during the differentiation stage showed reduced MHC-II molecule expression compared with BMDC that were generated in normal culture conditions. The BMDC generated in the presence of rHp-CPI also exhibited reduced expression of CD40, CD86 and MHC-II molecules and reduced interleukin-6 and tumour necrosis factor-α cytokine production when stimulated with Toll-like receptor ligand CpG. Activation of BMDC generated in normal conditions induced by lipopolysaccharide and CpG was also suppressed by rHp-CPI, as shown by reduced co-stimulatory molecule expression and cytokine production. Furthermore, BMDC treated with rHp-CPI before ovalbumin (OVA) antigen pulsing induced a weaker proliferation response and less interferon-γ production of OVA-specific CD4(+) T cells compared with BMDC without rHp-CPI pre-treatment. Adoptive transfer of rHp-CPI-treated and OVA-loaded BMDC to mice induced significantly lower levels of antigen-specific antibody response than the BMDC loaded with antigen alone. These results demonstrated that the CPI from nematode parasites is able to modulate differentiation and activation stages of BMDC. It also interferes with antigen and MHC-II molecule processing and Toll-like receptor signalling pathway, resulting in functionally deficient DC that induce a suboptimum immune response.