Immunization with a Lentiviral Vector Stimulates both CD4 and CD8 T Cell Responses to an Ovalbumin Transgene

Abstract

Lentiviral vectors encoding antigens are promising vaccine candidates because they transduce dendritic cells (DC) in vivo and prime CTL responses. Here we examine their stimulation of antigen-specific CD4(+) T cells, critical for protective immunity against tumors or infectious disease. We constructed lentiviral vectors (lentivectors) expressing ovalbumin, which was secreted (OVA), cytoplasmic (OVAcyt), or fused to either invariant chain (Ii-OVA) or transferrin receptor (TfR-OVA) sequences, targeting the MHC class II presentation pathway. Murine DC infected with the various lentivectors could stimulate OT-I (CD8(+), OVA TCR transgenic) T cells and all except OVAcyt could also stimulate OT-II (CD4(+), OVA TCR transgenic) T cells in vitro. Direct injection of the OVA-, Ii-OVA-, or TfR-OVA-expressing vectors into mice resulted in a CD4(+) T cell response, as shown by expansion of adoptively transferred OT-II T cells and upregulation of CD44 on these cells. The Ii-OVA vector was the most potent inducer of IFN-gamma-secreting CD4(+) and CD8(+) T cells and was the only vector to protect mice completely from challenge with OVA-expressing tumor cells. Therefore directly injected lentivectors can stimulate CD4(+) T cells; both CD4(+) and CD8(+) responses can be enhanced by targeting the antigen to the MHC class II pathway.

Recombinant lentivector as a genetic immunization vehicle for antitumor immunity

“…Consistent with in vitro results, recent studies show that direct administration of lentivector via intravenous or subcutaneous injection results in transduction of Ag presenting cells (APCs) including DCs in the spleen [57][58][59] , and in the draining lymph nodes 18,46,60 . Besides transduction of DCs in vivo, recombinant lentivector also results in transduction of B cells in the spleen after intravenous injection 57,59 or in the draining LNs after subcutaneous immunization.…”

“…Besides transduction of DCs in vivo, recombinant lentivector also results in transduction of B cells in the spleen after intravenous injection 57,59 or in the draining LNs after subcutaneous immunization. But, B cells isolated from mice immunized with recombinant lentivector did not induce naïve TCR transgenic T cells proliferation.…”

Lentiviral vectors for cancer immunotherapy: transforming infectious particles into therapeutics

“…109 Therefore it is crucial not only to evaluate the TAAspecific immune response but also the influence of the treatment on tumor growth. Whereas Rowe et al 110 showed significantly improved protection of direct administration of an OVA-encoding lentiviral vector against a subsequent tumor challenge, no data was shown about the therapeutic efficacy of this treatment. Using a similar OVA-encoding lentiviral vector we could show that direct administration of lentiviral vectors offers increased protection to a subsequent tumor challenge compared to DC vaccination and a significantly improved survival of tumor bearing mice.…”

“…[128][129][130] For direct administration of lentiviral vectors, several groups have shown that both a CTL response and an antigen-specific CD4 + T-cell response can be induced. 98,104,110 However, not much data is available on the role of CD4 + T-cell help in CTL induction. Esslinger et al showed that CD4 depletion reduces primary CTL response on direct administration of lentivirus.…”

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

“…Therefore, lentivectors have thus been proposed to be an ideal vector tool for vaccine delivery. 20,[24][25][26][27][28][29][30][31][32][33] Based on the study of Sindbis virus, a member of the Alphavirus genus and the Togaviride family, we have reported a mutant Sindbis virus glycoprotein, (SVGmu) which can specifically bind to DC-specific intracellular adhesion molecule (ICAM) 3 grabbing non-integrin (DC-SIGN, CD209). 34 DC-SIGN is a C-type lectin-like receptor and is expressed on DCs and macrophages.…”