MyD88 Signaling in B Cells Regulates the Production of Th1-dependent Antibodies to AAV

被引:47
作者
Sudres, Muriel [1 ]
Cire, Severine [1 ]
Vasseur, Virginie [2 ]
Brault, Lea [2 ]
Da Rocha, Sylvie [1 ]
Boisgerault, Florence [1 ]
Le Bec, Christine
Gross, David Alexandre [3 ]
Blouin, Veronique [4 ]
Ryffel, Bernard [2 ]
Galy, Anne [1 ,5 ]
机构
[1] Genethon, INSERM, U951, Mol Immunol & Innovat Biotherapies, F-91002 Evry, France
[2] CNRS, UMR 6218, F-45071 Orleans, France
[3] Univ Paris 05, INSERM, Fac Med, U1013, Paris, France
[4] INSERM, UMR649, Therapeut Res Inst, Nantes, France
[5] Univ Evry, UMR S951, Genethon, Evry, France
关键词
TOLL-LIKE RECEPTORS; ADENOASSOCIATED VIRUS VECTORS; INNATE IMMUNE-RESPONSES; GENE-THERAPY; ANTIGEN PRESENTATION; SKELETAL-MUSCLE; VIRAL VECTORS; T-CELLS; LIVER; MICE;
D O I
10.1038/mt.2012.101
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The administration of recombinant adeno-associated viral vectors (rAAV) for gene transfer induces strong humoral responses through mechanisms that remain incompletely characterized. To investigate the links between innate and adaptive immune responses to the vector, rAAVs were injected intravenously into mice deficient in cell-intrinsic components of innate responses (Toll-like receptors (TLRs), type-1 interferon (IFN) or inflammasome signaling molecules) and AAV-specific antibodies were measured. Of all molecules tested, only MyD88 was critically needed to mount immunoglobulin G (IgG) responses since MyD88(-/-) mice failed to develop high levels of AAV-specific IgG2 and IgG3, regardless of capsid serotype injected. None of the TLRs tested was essential here, but TLR9 ensured a Th1-biased antibody responses. Indeed, capsid-specific Th1 cells were induced upon injection of rAAV1, as directly confirmed with an epitope-tagged capsid, and the priming and development of these Th1 cells required T cell-extrinsic MyD88. Cell transfer experiments showed that autonomous MyD88 signaling in B cells, but not T cells, was sufficient to produce Th1-dependent IgGs. Therefore, rAAV triggers innate responses, at least via B cells, controlling the development of capsid-specific Th1-driven antibodies. MyD88 emerges as a critical and pivotal regulator of both T- and B-cell adaptive immunity against AAV.
引用
收藏
页码:1571 / 1581
页数:11
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