CTL induction by cross‐priming is restricted to immunodominant epitopes

Abstract

CTL are induced by two pathways, i.e. direct priming, where tumor cells present tumor antigens to naïve specific CTL, and cross-priming, where professional APC cross-present captured tumor antigens to CTL. Here, we examined direct priming versus cross-priming after immunizing (H-2 b  H-2 d ) F1 mice with either H-2 b or H-2 d positive tumor cells transfected with the GP or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV). Cross-priming was observed for the immunodominant epitopes LCMV-gp33 andnp118, although direct induction resulted in higher CTL frequencies. In contrast, CTL specific for the subdominant epitopes LCMV-gp283 or -np396 were induced only if epitopes were presented directly on MHC class I molecules of the immunizing cell. The broader repertoire and the higher CTL frequencies induced after vaccination with haplotype-matched tumor cells resulted in more efficient anti-tumor and antiviral protection. Firstly, our results indicate that certain virus and tumor antigens may not be detected by CD8 1 T cells because of impaired cross-priming. Secondly, efficient cross-priming contributes to the immunodominant nature of a tumor-specific CTL epitope. Thirdly, vaccine strategies using autologous or syngenic antigen-expressing cells induce a broader repertoire of tumor-specific CTL and higher CTL frequencies.Key words: CD8 T cells . Cross presentation/priming . Tumor immunology IntroductionProfessional APC (pAPC) capture cells in the periphery, migrate to secondary lymphoid organs, cross-present the specific antigen and activate naïve CTL. Cross-priming enables the immune system to detect and respond to pathogens, tumors and tissue antigens that are exclusively expressed outside of secondary lymphoid organs. Cross-priming may be essential for the immunosurveillance of tumors, since most tumor cells lack costimulatory molecules and thus cannot efficiently stimulate protective anti-tumoral CTL immunity [1][2][3]. Alternatively, tumor cells directly present the internally synthesized tumor antigen via MHC class I molecules and activate naïve tumorspecific CTL [2,4]. This direct priming pathway requires that tumor cells reach secondary lymphoid organs. Different cellular pathways in the cross-presentation of exogenous antigen have been characterized. They can be separated into TAP-dependent and TAP-independent mechanisms [5,6]. Current literature favors the view that TAP-dependent mechanisms are dominating in vivo [6].Several studies have shown that stable cellular proteins in particulate form are the major source of cross-presented antigens in vivo, whereas soluble proteins, peptides, HSP-peptide complexes, RNA and DNA seem to play only a minor role in crosspresentation [7][8][9]. Although different cell types, including B cells, macrophages and endothelial cells, have been reported to have the capacity to cross-present antigens, CD81 DC are the predominant cell population capturing and cross-presenting tumor antigens 704 [10][11][12][13]. The maturation of DC and the efficiency of cross-priming c...

Antibody-Targeted NY-ESO-1 to Mannose Receptor or DEC-205 In Vitro Elicits Dual Human CD8+ and CD4+ T Cell Responses with Broad Antigen Specificity

“…2C). Similar selective cross-presentation of epitopes from an exogenous protein in contrast to nonselective presentation from an endogenous protein was reported (39,40). To understand the mechanism for epitope-dependent presentation after targeting exogenous Ags to cell surface receptors, it is interesting to investigate the route of Ag cross-presentation after internalization via targeting molecules.…”

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

“…The contribution of multiple epitopes from viral proteins to the cross-presentation pathway after infections is not well understood. In fact, much of what is known about the cross-presentation of virus antigens is derived from studies relying on antigen donor cells (ADC) transfected with a single virus protein [7][8][9][10]. The ability of antigens to escape cytosolic degradation in ADC is important during cross-presentation [7,[11][12][13].…”

“…The ability of antigens to escape cytosolic degradation in ADC is important during cross-presentation [7,[11][12][13]. Interestingly, it appears that the capacity of an epitope to access cross-priming may support its immunodominance when considering the overall hierarchy [8,10,14]. Collectively, these findings seem to conflict with the immunodominant status of GP33 because this epitope is located in the signal sequence of the glycoprotein (lymphocytic choriomeningitis virus (LCMV)-GP) [15] and may not be able to cross-prime CTL [12].…”

Hepatitis B Surface Antigen-based Vaccines for Human Neoplastic Disease

“…APCs at the site of immunisation are either directly transfected with DNA molecules (Chattergoon et al, 1998), allowing them to express antigen encoded by the DNA endogenously or they can acquire antigen indirectly via cross presentation (Datta & Raz, 2005;Pavelic et al, 2009). Once the APCs are activated they then prime CD8 + T-cells and activate CD4 + T-cells either at the site of immunisation or at draining lymph nodes, resulting in large numbers of antigen-specific CD8 + T-cells which can be directly cytopathic to cells expressing the antigen (Ando et al, 1994) and can protect against pathogenic infections (Thomson et al, 1998;Roy et al, 2000a;Woo et al, 2006).…”

“…The small amount of DNA which is taken up by cells at the site of immunisation occurs in myocytes, pAPCs such as DCs and nonprofessional APCs such as monocytes (Chattergoon et al, 2000;Dupuis et al, 2000). APCs at the site of immunisation are either directly transfected with DNA molecules (Chattergoon et al, 1998), allowing them to express antigen endogenously or they can acquire antigen indirectly via cross presentation (Datta & Raz, 2005;Pavelic et al, 2009). Once antigen is acquired, APCs express antigen encoded in the DNA vaccine, which is subsequently degraded intracellularly by the proteasome.…”