Induction and activation of human Th17 by targeting antigens to dendritic cells via dectin-1.

Abstract

Recent compelling evidence indicates that Th17 confer host immunity against a variety of microbes, including extracellular and intracellular pathogens. Therefore, understanding mechanisms for the induction and activation of Ag-specific Th17 is important for the rational design of vaccines against pathogens. To study this, we employed an in vitro system in which influenza hemagglutinin (HA) 1 was delivered to dendritic cells (DCs) via Dectin-1 using anti-human Dectin-1 (hDectin-1)-HA1 recombinant fusion proteins. We found that healthy individuals maintained broad ranges of HA1-specific memory Th17 that were efficiently activated by DCs targeted with anti-hDectin-1-HA1. Nonetheless, these DCs were not able to induce a significant level of HA1-specific Th17 responses even in the presence of the Th17-promoting cytokines IL-1β and IL-6. We further found that the induction of surface IL-1R1 expression by signals via TCRs and common γ-chain receptors was essential for naive CD4(+) T cell differentiation into HA1-specific Th17. This process was dependent on MyD88, but not IL-1R-associated kinase 1/4. Thus, interruptions in STAT3 or MyD88 signaling led to substantially diminished HA1-specific Th17 induction. Taken together, the de novo generation of pathogen-specific human Th17 requires complex, but complementary, actions of multiple signals. Data from this study will help us design a new and effective vaccine strategy that can promote Th17-mediated immunity against microbial pathogens.

• Authors: Dorothée Duluc, HyeMee Joo, Ling Ni, Wenjie Yin, Katherine Upchurch, Dapeng Li, Yaming Xue, Peter Klucar, Sandra Zurawski, Gerard Zurawski, SangKon Oh
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 12 Pg. 5776-88 (Jun 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24835401 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Antigens, Viral
• CLEC7A protein, human
• H1N1 virus hemagglutinin
• Hemagglutinin Glycoproteins, Influenza Virus
• IL1B protein, human
• IL6 protein, human
• Interleukin-1beta
• Interleukin-6
• Lectins, C-Type
• MYD88 protein, human
• Myeloid Differentiation Factor 88

Topics

• Antigens, Viral (immunology)
• Dendritic Cells (cytology, immunology)
• Female
• Hemagglutinin Glycoproteins, Influenza Virus (immunology)
• Humans
• Interleukin-1beta (immunology)
• Interleukin-6 (immunology)
• Lectins, C-Type (immunology)
• Male
• Myeloid Differentiation Factor 88 (immunology)
• Th17 Cells (cytology, immunology)