Chronic helminth infection promotes immune regulation in vivo through dominance of CD11cloCD103- dendritic cells

Katherine A Smith, Kristin Hochweller, Günter J Hämmerling, Louis Boon, Andrew S MacDonald, Rick M Maizels

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)7098-7109
Number of pages12
JournalJournal of Immunology
Volume186
Issue number12
DOIs
Publication statusPublished - 15 Jun 2011

Keywords

  • Animals
  • Antigens, CD
  • Antigens, CD11
  • Cell Count
  • Chronic Disease
  • Dendritic Cells
  • Helminthiasis
  • Immunity
  • Immunophenotyping
  • Integrin alpha Chains
  • Intestinal Diseases, Parasitic
  • Mice
  • Nematospiroides dubius
  • T-Lymphocytes, Regulatory

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