Induction and activation of human Th17 by targeting antigens to dendritic cells via dectin-1.
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.
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
Dorothée
D
Duluc
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
HyeMee
H
Joo
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
Ling
L
Ni
Baylor Institute for Immunology Research, Dallas, TX 75204; and Baylor University, Institute for Biomedical Studies, Waco, TX 76706.
Wenjie
W
Yin
Baylor Institute for Immunology Research, Dallas, TX 75204; and Baylor University, Institute for Biomedical Studies, Waco, TX 76706.
Katherine
K
Upchurch
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
Dapeng
D
Li
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
Yaming
Y
Xue
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
Peter
P
Klucar
Baylor Institute for Immunology Research, Dallas, TX 75204; and.
Sandra
S
Zurawski
Baylor Institute for Immunology Research, Dallas, TX 75204; and Baylor University, Institute for Biomedical Studies, Waco, TX 76706.
Gerard
G
Zurawski
Baylor Institute for Immunology Research, Dallas, TX 75204; and Baylor University, Institute for Biomedical Studies, Waco, TX 76706 sangkono@baylorhealth.edu.
SangKon
S
Oh
D000956:Antigens, Viral / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology*; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D037181:Lectins, C-Type / Q000276:immunology*; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D000099181:Dectin-1
D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D053583:Interleukin-1beta; D015850:Interleukin-6; D037181:Lectins, C-Type; D053594:Myeloid Differentiation Factor 88; C546929:CLEC7A protein, human; D000099181:Dectin-1; C543345:H1N1 virus hemagglutinin; C508585:IL1B protein, human; C508600:IL6 protein, human; C507779:MYD88 protein, human