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PLoS One. 2016 Dec 15;11(12):e0167693. doi: 10.1371/journal.pone.0167693. eCollection 2016.

Determinants of Divergent Adaptive Immune Responses after Airway Sensitization with Ligands of Toll-Like Receptor 5 or Toll-Like Receptor 9.

Author information

1
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
2
Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, United States of America.
3
Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, United States of America.
4
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
5
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America.
6
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California, United States of America.

Abstract

Excessive type 2 helper T cell responses to environmental antigens can cause immunopathology such as asthma and allergy, but how such immune responses are induced remains unclear. We studied this process in the airways by immunizing mice intranasally with the antigen ovalbumin together with either of two Toll-like receptor (TLR) ligands. We found the TLR5 ligand flagellin promoted a type 2 helper T cell response, whereas, a TLR9 ligand CpG oligodeoxyribonucleotide (ODN) promoted a type 1 helper T cell response. CpG ODN induced mRNA encoding interleukin (IL)-12 p40, whereas, flagellin caused IL-33 secretion and induced mRNAs encoding IL-1 and thymic stromal lymphopoietin (TSLP). By using mice deficient in the TLR and IL-1R signaling molecule, myeloid differentiation primary response 88 (MyD88), in conventional dendritic cells (cDCs) and alveolar macrophages (AMs), and by cell sorting different lung populations after 2 hours of in vivo stimulation, we characterized the cell types that rapidly produced inflammatory cytokines in response to TLR stimulation. CpG ODN was likely recognized by TLR9 on cDCs and AMs, which made mRNA encoding IL-12. IL-12 was necessary for the subsequent innate and adaptive interferon-γ production. In contrast, flagellin stimulated multiple cells of hematopoietic and non-hematopoietic origin, including AMs, DCs, monocytes, and lung epithelial cells. AMs were largely responsible for IL-1α, whereas lung epithelial cells made TSLP. Multiple hematopoietic cells, including AMs, DCs, and monocytes contributed to other cytokines, including IL-1β and TNFα. MyD88-dependent signals, likely through IL-1R and IL-33R, and MyD88-independent signals, likely from TSLP, were necessary in cDCs for promotion of the early IL-4 response by CD4 T cells in the draining lymph node. Thus, the cell types that responded to TLR ligands were a critical determinant of the innate cytokines produced and the character of the resulting adaptive immune response in the airways.

PMID:
27977701
PMCID:
PMC5157987
DOI:
10.1371/journal.pone.0167693
[Indexed for MEDLINE]
Free PMC Article

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