TY - JOUR
T1 - Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets
AU - Kastenmüller, Kathrin
AU - Wille-Reece, Ulrike
AU - Lindsay, Ross W.B.
AU - Trager, Lauren R.
AU - Darrah, Patricia A.
AU - Flynn, Barbara J.
AU - Becker, Maria R.
AU - Udey, Mark C.
AU - Clausen, Björn E.
AU - Igyarto, Botond Z.
AU - Kaplan, Daniel H.
AU - Kastenmüller, Wolfgang
AU - Germain, Ronald N.
AU - Seder, Robert A.
PY - 2011/5/2
Y1 - 2011/5/2
N2 - The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4+ and CD8+ T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8 -DEC205+CD103-CD326- langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8+ T cells as CD11c+CD8+ DCs. Moreover, these cells also influenced Th1 CD4+ T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines.
AB - The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4+ and CD8+ T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8 -DEC205+CD103-CD326- langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8+ T cells as CD11c+CD8+ DCs. Moreover, these cells also influenced Th1 CD4+ T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines.
UR - http://www.scopus.com/inward/record.url?scp=79955505656&partnerID=8YFLogxK
U2 - 10.1172/JCI45416
DO - 10.1172/JCI45416
M3 - Article
C2 - 21540549
AN - SCOPUS:79955505656
SN - 0021-9738
VL - 121
SP - 1782
EP - 1796
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -