Impairment of dendritic cell function by excretory-secretory products: a potential mechanism for nematode-induced immunosuppression.
To determine whether helminth-derived products modulate dendritic cell (DC) function, we investigated the effects of excretory-secretory products (ES) and adult worm homogenate (AWH) derived from the gastrointestinal nematode Heligmosomoides polygyrus (Hp) on murine bone marrow-derived DC (BMDC). Compared to the TLR9 ligand CpG, Hp-derived products alone failed to induce DC activation. ES, but not AWH, inhibited BMDC cytokine and chemokine production and co-stimulatory molecule expression (CD40, CD86 and MHC class II) induced by TLR ligation. TLR ligand-independent, PMA-induced DC activation was unaffected by ES. Recipients of ES-treated BMDC pulsed with OVA had suppressed Ab responses in vivo, irrespective of the Th1 or Th2 isotype affiliation, compared to recipients of control OVA-pulsed BMDC. Importantly, suppression occurred even in the presence of the potent type 1 adjuvant CpG. In contrast to untreated OVA-pulsed BMDC, ES-treated BMDC pulsed with OVA had reduced co-stimulatory molecule and cytokine expression. CD4(+)CD25(+)Foxp3(-) T cells, which secreted high IL-10 levels, were generated in co-cultures of OT-II OVA-specific TCR-transgenic CD4(+) T cells and ES-treated BMDC. These IL-10-secreting T cells suppressed effector CD4(+) T cell proliferation and IFN-gamma production, the latter effect mediated by an IL-10-dependent mechanism. Together, these results demonstrate that nematode ES impaired DC function and suppressed both Th1 and Th2 adaptive immune responses possibly by inducing regulatory T cells.
Segura
Mariela
M
Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, McGill University, Montreal, Québec, Canada.
Su
Zhong
Z
Piccirillo
Ciriaco
C
Stevenson
Mary M
MM
D000276:Adjuvants, Immunologic; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015801:Helminth Proteins / Q000276:immunology*; D007108:Immune Tolerance; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009351:Nematospiroides dubius / Q000276:immunology / Q000472:pathogenicity; D017206:Strongylida Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D000947:Antigens, Helminth; D015801:Helminth Proteins