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Genetic immunization with GPI-anchored anthrax protective antigen raises combined CD1d- and MHC II-restricted antibody responses by natural killer T cell-mediated help.

Abstract：

:Studies have demonstrated that lipid rafts ultimately regulate the endocytosis of anthrax toxin via clathrin dependent pathway. Interestingly, GPI-anchored protein rich rafts have also been shown to be transported down to the endocytic pathway to reducing late endosomes. Taking advantage of this parallelism, we tried translating the anthrax toxin natural intoxication mechanism by administering a DNA chimera that encoded protective antigen attached to a mammalian GPI-anchor sequence at its C-terminus (pGPI-PA63). We also designed a chimera that had an additional N-terminal TPA leader sequence (pTPA.GPI-PA63) with an aim to target GPI-PA63 to ER where new CD1 molecules are synthesized. Analysis of antibody titers demonstrated successful priming and potential IgG titers after the first boost. In vitro cell proliferation studies in the presence of GPI-attached PA63 peptides revealed that there was a clonal expansion of CD4(+) NK1.1(+) helper T cell population which rapidly produced IL-4 in response to T cell receptor ligation. These cells provided direct B cell help that aided IgG formation. Effector responses generated by NKT cells were found to be MHC II-independent and CD1d-restricted. In addition, the group pTPA.GPI-PA63 also displayed low magnitude MHC-II restricted (CD1d-independent) NKT cell and CD4(+) T cell helper responses in response to non-GPI attached PA63 peptides which overall resulted in the heightened responses seen for this group. Importantly, DNA vaccination mediated the generation of high avidity neutralizing antibodies that mediated protection against lethal toxin challenge.

journal_name

Vaccine

journal_title

Vaccine

authors

Midha S,Bhatnagar R

doi

10.1016/j.vaccine.2009.01.042

subject

Has Abstract

pub_date

2009-03-10 00:00:00

pages

1700-9

issue

11

eissn

0264-410X

issn

1873-2518

pii

S0264-410X(09)00132-7

journal_volume

27

pub_type

杂志文章

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