Myeloid dendritic cells are primed in allergic asthma for thymic stromal lymphopoietin-mediated induction of Th2 and Th9 responses

Allergy. 2014 Aug;69(8):1068-76. doi: 10.1111/all.12435. Epub 2014 Jun 3.

Abstract

Background: Type 1 myeloid dendritic cells (mDCs) contribute to inception of allergic asthma (AA) and are regulated by epithelial-derived cytokines.

Objectives: To evaluate whether mDCs from AA patients are primed for thymic stromal lymphopoietin (TSLP)-driven responses.

Methods: mDCs from 18 AA patients and 15 controls were purified using immunomagnetic sorting. Cells were pulsed with TSLP or Dermatophagoides pteronyssinus (Der p) allergen, before FACS phenotyping and co-culture with allogeneic CD4+ T cells. Bronchial biopsies from 15 AA patients and four controls were immunostained for CD1c and TSLP receptor (TSLPR).

Results: Allergic asthma patients had a higher proportion of TSLPR+ mDCs, in blood and bronchial mucosa. When compared to mDCs from controls, both TSLP- and Der p-pulsed blood mDCs from AA patients induced increased polarization of CD4+ T cells into Th2 cells (IL-5, IL-13, and GATA3+), while only TSLP-mDCs promoted Th9 cells (IL-9 and PU.1+ /IRF4+). In addition, OX40L was induced upon TSLP stimulation and was required for the induction of Th2, but not Th9, cells. In contrast, development of Th9 cells in this model depended on TGF-β1.

Conclusions: Our data indicate overlapping but partially distinct effects of TSLP and Der p allergen pathways, showing that DCs are primed in human asthma for TSLP-driven induction of both Th2 and Th9 cells. This novel TSLP/mDC/Th9 axis operates through a distinct, OX40L-independent pathway. These data further highlight the TSLP pathway as a relevant target in human asthma.

Keywords: Th9; asthma; interleukin-9; myeloid dendritic cells; thymic stromal lymphopoietin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Dermatophagoides / immunology
  • Arthropod Proteins / immunology
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / metabolism*
  • Case-Control Studies
  • Cysteine Endopeptidases / immunology
  • Cytokines / metabolism*
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Gene Expression
  • Humans
  • OX40 Ligand / antagonists & inhibitors
  • OX40 Ligand / metabolism
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism*
  • Up-Regulation

Substances

  • Antigens, Dermatophagoides
  • Arthropod Proteins
  • CRLF2 protein, human
  • Cytokines
  • OX40 Ligand
  • Receptors, Cytokine
  • Cysteine Endopeptidases
  • Dermatophagoides pteronyssinus antigen p 1
  • thymic stromal lymphopoietin