TY - JOUR
T1 - Induction of adaptive immunity by flagellin does not require robust activation of innate immunity
AU - Sanders, Catherine J.
AU - Franchi, Luigi
AU - Yarovinsky, Felix
AU - Uematsu, Satoshi
AU - Akira, Shizuo
AU - Núñez, Gabriel
AU - Gewirtz, Andrew T.
PY - 2009
Y1 - 2009
N2 - The ability of TLR agonists to promote adaptive immune responses is attributed to their ability to robustly activate innate immunity. However, it has been observed that, for adjuvants in actual use in research and vaccination, TLR signaling is dispensable for generating humoral immunity. Here, we examined the role of TLR5 and MyD88 in promoting innate and humoral immunity to flagellin using a prime/boost immunization regimen. We observed that eliminating TLR5 greatly reduced flagellin-induced cytokine production, except for IL-18, and ablated DC maturation but did not significantly impact flagellin's ability to promote humoral immunity. Elimination of MyD88, which will ablate signaling through TLR and IL-Iβ/IL-18 generated by Nod-like receptors, reduced, but did not eliminate flagellin's promotion of humoral immunity. in contrast, loss of the innate immune receptor for profilin-like protein (PLP), TLR11, greatly reduced the ability of PLP to elicit humoral immunity. Together, these results indicate that, firstly, the degree of innate immune activation induced by TLR agonists may be in great excess of that needed to promote humoral immunity and, secondly, there is considerable redundancy in mechanisms that promote the humoral immune response upon innate immune recognition of flagellin. Thus, it should be possible to design innate immune activators that are highly effective vaccine adjuvants yet avoid the adverse events associated with systemic TLR activation.
AB - The ability of TLR agonists to promote adaptive immune responses is attributed to their ability to robustly activate innate immunity. However, it has been observed that, for adjuvants in actual use in research and vaccination, TLR signaling is dispensable for generating humoral immunity. Here, we examined the role of TLR5 and MyD88 in promoting innate and humoral immunity to flagellin using a prime/boost immunization regimen. We observed that eliminating TLR5 greatly reduced flagellin-induced cytokine production, except for IL-18, and ablated DC maturation but did not significantly impact flagellin's ability to promote humoral immunity. Elimination of MyD88, which will ablate signaling through TLR and IL-Iβ/IL-18 generated by Nod-like receptors, reduced, but did not eliminate flagellin's promotion of humoral immunity. in contrast, loss of the innate immune receptor for profilin-like protein (PLP), TLR11, greatly reduced the ability of PLP to elicit humoral immunity. Together, these results indicate that, firstly, the degree of innate immune activation induced by TLR agonists may be in great excess of that needed to promote humoral immunity and, secondly, there is considerable redundancy in mechanisms that promote the humoral immune response upon innate immune recognition of flagellin. Thus, it should be possible to design innate immune activators that are highly effective vaccine adjuvants yet avoid the adverse events associated with systemic TLR activation.
KW - Adjuvant
KW - Cytokines
KW - DC
KW - Profilin-like protein
KW - TLR
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U2 - 10.1002/eji.200838804
DO - 10.1002/eji.200838804
M3 - Article
C2 - 19152336
AN - SCOPUS:60749119489
SN - 0014-2980
VL - 39
SP - 359
EP - 371
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 2
ER -