Targeting Antigens to Human Dendritic Cells via Dectin-1 Elicits Potent Antigen-specific Th17 CD4+ T Cells That Express Mucosal Homing Receptors (100.39)

Abstract

Abstract Emerging evidence indicates important roles of IL-17-producing (Th17) CD4+ T cells in protective immunity against microbial pathogens, including influenza viruses. Thus we tested the magnitudes and spectrum of influenza viral hemagglutinin subunit 1 (HA1)-specific Th17 CD4+ T cells in healthy donors by targeting HA1 to dendritic cells (DCs) via Dectin-1 using recombinant fusion proteins of agonistic anti-Dectin-1 fused to HA1 (anti-Dectin-1-HA1). Our data show that healthy individuals maintain broad ranges of influenza HA1-specific Th17 CD4+ T cells expressing CCR4 and CCR6. Interestingly, HA1-specific Th17 CD4+ T cells were distinguished from other Th17 CD4+ T cells by expressing increased levels of CCR9 and decreased levels of CD161. We further found that DCs activated through hDectin-1 upregulated other mucosal homing receptors, beta7 integrin, CCR4, and CCR9 on the surface of HA1-specific Th17 CD4+ T cells. Such HA1-specific Th17 CD4+ T cell responses were greatly enhanced by targeting DCs with anti-Dectin-1-HA1 in the presence of TLR2 ligands. This enhancement was mainly due to the expansion of pre-existing HA1-specific memory Th17 CD4+ T cells that express IL-1R1, but not naïve CD4+ T cells which do not. Induction of IL-1R1 on naïve CD4+ T cells required for priming HA1-specific Th17 CD4+ T cells. Taken together, we conclude that antigen targeting to DCs via Dectin-1 could mount potent protective immunity against microbial pathogens, including influenza viruses.