Journal
JOURNAL OF INNATE IMMUNITY
Volume 7, Issue 3, Pages 302-314Publisher
KARGER
DOI: 10.1159/000369273
Keywords
Adeno-associated viral vectors; Gene therapy; Immune responses; Innate immunity; TLR9; MyD88; Antibody; CD8+T cell
Categories
Funding
- National Institutes of Health [P01 HD078810, R01 AI51390, R00HL098692, R01 HL087836]
- Howard Hughes Medical Institute
- NIH [T32 AI 007110]
- University of Florida College of Medicine
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The immune system represents a significant barrier to successful gene therapy with adeno-associated viral (AAV) vectors. In particular, adaptive immune responses to the viral capsid or the transgene product are of concern. The sensing of AAV by toll-like receptors (TLRs) TLR2 and TLR9 has been suggested to play a role in innate immunity to the virus and may also shape subsequent adaptive immune responses. Here, we investigated the functions of TLR2, TLR9 and the downstream signaling adaptor MyD88 in antibody and CD8+ T-cell responses. Antibody formation against the transgene product occurred largely independently of TLR signaling following gene transfer with AAV1 or AAV2 vectors, whereas loss of signaling through the TLR9-MyD88 pathway substantially reduced CD8+ T-cell responses. In contrast, MyD88 (but neither of the TLRs) regulated antibody responses to capsid. B cell-intrinsic MyD88 was required for the formation of anti-capsid IgG2c independently of vector serotype or route of administration. However, MyD88(-/-) mice instead produced anti-capsid IgG1 that emerged with delayed kinetics but nonetheless completely prevented in vivo readministration. We conclude that there are distinct roles for TLR9 and MyD88 in promoting adaptive immune responses to AAV-mediated gene transfer and that there are redundant MyD88-dependent and MyD88-independent mechanisms that stimulate neutralizing antibody formation against AAV. (C) 2015 S. Karger AG, Basel
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