Inhibition of invariant chain expression in dendritic cells presenting endogenous antigens stimulates CD4+ T-cell responses and tumor immunity

Abstract

Induction of potent and sustained antiviral or antitumor immunity is dependent on the efficient activation of CD8+ and CD4+ T cells. While dendritic cells constitute a powerful platform for stimulating cellular immunity, presentation of endogenous antigens by dendritic cells transfected with nucleic acid-encoded antigens favors the stimulation of CD8+ T cells over that of CD4+ T cells. A short incubation of mRNA-transfected dendritic cells with antisense oligonucleotides directed against the invariant chain enhances the presentation of mRNA-encoded class II epitopes and activation of CD4+ T-cell responses in vitro and in vivo. Immunization of mice with the antisense oligonucleotide-treated dendritic cells stimulates a more potent and longer lasting CD8+ cytotoxic T-cell (CTL) response and enhances the antitumor efficacy of dendritic cell-based tumor vaccination protocols. Transient inhibition of invariant chain expression represents a simple and general method to enhance the stimulation of CD4+ T-cell responses from endogenous antigens. (Blood. 2003;102:4137-4142)

Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions

“…Lack of invariant chain expression, which frequently occurs in immune-privileged sites, favors the presentation of endogenous as opposed to exogenous peptides that may alter details of the inflammatory response. 31,32 Investigation of this matter will be the focus of future research that may have implications regarding different mechanisms of lymphomagenesis at different anatomic locations, a previously unexplored area of DLBCL biology. For personal use only.…”

Manipulating dendritic cell biology for the active immunotherapy of cancer

“…Cross-presentation can also be enhanced by targeting DC surface receptors such as DEC-205, 20 loading DCs with killed cells or cell lysates or by stimulating DCs with TLR agonists that induce cross presentation 49 ( Figure 5). Transfected RNA, which primarily targets MHC I, may also be targeted to MHC II by incubating the transfected DCs with antisense oligonucleotides to the MHC II-associated Ii protein 137 or by using fusion constructs carrying an endosomal/lysosomal sorting signal. 138 …”

NK Cells Negatively Regulate Antigen Presentation and Tumor-Specific CTLs in a Syngeneic Lymphoma Model

“…RMA/t-OVA cells express H-2K b /OVA peptide complexes on their surfaces (Fig. 1A) and were made by retrovirally transducing RMA cells with a vector containing a truncated OVA gene, so the OVA protein cannot be secreted and remains an intracellular tumor Ag (24,25). Like the RMA parental cell line, RMA/t-OVA cells do not express NKG2D ligands (Fig.…”

“…RMA is a C57BL/6 T cell lymphoma. RMA/t-OVA was made by retroviral transduction with a vector containing a truncated OVA gene where nucleotides encoding aa 1-40 (the leader peptide) were removed (24,25). P815 cells expressing H-2K b were made by retroviral transduction.…”