title: Chronic helminth infection promotes immune regulation in vivo through dominance of CD11cloCD103- dendritic cells.
abstract: Gastrointestinal helminth infections are extremely prevalent in many human populations and are associated with downmodulated immune responsiveness. In the experimental model system of Heligmosomoides polygyrus, a chronic infection establishes in mice, accompanied by a modulated Th2 response and increased regulatory T cell (Treg) activity. To determine if dendritic cell (DC) populations in the lymph nodes draining the intestine are responsible for the regulatory effects of chronic infection, we first identified a population of CD11c(lo) nonplasmacytoid DCs that expand after chronic H. polygyrus infection. The CD11c(lo) DCs are underrepresented in magnetic bead-sorted preparations and spared from deletion in CD11c-diptheria toxin receptor mice. After infection, CD11c(lo) DCs did not express CD8, CD103, PDCA, or Siglec-H and were poorly responsive to TLR stimuli. In DC/T cell cocultures, CD11c(lo) DCs from naive and H. polygyrus-infected mice could process and present protein Ag, but induced lower levels of Ag-specific CD4(+) T cell proliferation and effector cytokine production, and generated higher percentages of Foxp3(+) T cells in the presence of TGF-β. Treg generation was also dependent on retinoic acid receptor signaling. In vivo, depletion of CD11c(hi) DCs further favored the dominance of the CD11c(lo) DC phenotype. After CD11c(hi) DC depletion, effector responses were inhibited dramatically, but the expansion in Treg numbers after H. polygyrus infection was barely compromised, showing a significantly higher regulatory/effector CD4(+) T cell ratio compared with that of CD11c(hi) DC-intact animals. Thus, the proregulatory environment of chronic intestinal helminth infection is associated with the in vivo predominance of a newly defined phenotype of CD11c(lo) tolerogenic DCs.
authors.affiliation: Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Smith
authors.forename: Kristin
authors.initials: K
authors.lastname: Hochweller
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Andrew S
authors.initials: AS
authors.lastname: MacDonald
authors.forename: Rick M
authors.initials: RM
authors.lastname: Maizels
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D018845:CD11 Antigens / Q000276:immunology; D002452:Cell Count; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology*; D006373:Helminthiasis / Q000276:immunology*; D007109:Immunity; D016130:Immunophenotyping; D039001:Integrin alpha Chains / Q000276:immunology; D007411:Intestinal Diseases, Parasitic / Q000276:immunology*; D051379:Mice; D009351:Nematospiroides dubius / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018845:CD11 Antigens; D039001:Integrin alpha Chains; C091367:alpha E integrins