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Dorothée Duluc, HyeMee Joo, Ling Ni, Wenjie Yin, Katherine Upchurch, Dapeng Li, Yaming Xue, Peter Klucar, Sandra Zurawski, Gerard Zurawski, SangKon Oh, Induction and Activation of Human Th17 by Targeting Antigens to Dendritic Cells via Dectin-1, The Journal of Immunology, Volume 192, Issue 12, June 2014, Pages 5776–5788, https://doi.org/10.4049/jimmunol.1301661
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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.
