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.2012 Nov 26:3:348.
doi: 10.3389/fimmu.2012.00348. eCollection 2012.

MHC class I cross-presentation by dendritic cells counteracts viral immune evasion

Affiliations

MHC class I cross-presentation by dendritic cells counteracts viral immune evasion

Katrin Nopora et al. Front Immunol..

Abstract

DCs very potently activate CD8(+) T cells specific for viral peptides bound to MHC class I molecules. However, many viruses have evolved immune evasion mechanisms, which inactivate infected DCs and might reduce priming of T cells. Then MHC class I cross-presentation of exogenous viral Ag by non-infected DCs may become crucial to assure CD8(+) T cell responses. Although many vital functions of infected DCs are inhibited in vitro by many different viruses, the contributions of cross-presentation to T cell immunity when confronted with viral immune inactivation in vivo has not been demonstrated up to now, and remains controversial. Here we show that priming of Herpes Simplex Virus (HSV)-, but not murine cytomegalovirus (mCMV)-specific CD8(+) T cells was severely reduced in mice with a DC-specific cross-presentation deficiency. In contrast, while CD8(+) T cell responses to mutant HSV, which lacks crucial inhibitory genes, also depended on CD8α(+) DCs, they were independent of cross-presentation. Therefore HSV-specific CTL-responses entirely depend on the CD8α(+) DC subset, which present via direct or cross-presentation mechanisms depending on the immune evasion equipment of virus. Our data establish the contribution of cross-presentation to counteract viral immune evasion mechanisms in some, but not all viruses.

Keywords: cross-priming; dendritic cells; immune evasion.

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Figures

Figure 1
Figure 1
Deletion of HSV-1 immune evasion genes rescues APC-functions of infected DCsin vitro. BMDC were infected with HSVwt, HSVmut, or mock-infected and utilized to stimulate CFSE-labeled TCR-transgenic HSVgB-specific CD8+ gBT-I T cells(A). In addition DCs were loaded with the LCMVgp33-41 peptide at the indicated concentration and cultured with CFSE-labeled TCR-transgenic gp33-41-specific CD8+ P14 T cells(B). Appropriate conditions for DC: Tcell ratio and peptide concentration were determined by titration [(A,B) side insets]. Main graphs show results of CFSE-profiles of gated CD8+ T cells for one experiment out of four with similar results in which 2500 DCs were cultured with 5 × 104 CFSE-labeled T cells for 4 days and peptide concentration was 0.1 ng/ml.
Figure 2
Figure 2
Batf3-ko mice cannot mount HSV-specific CD8 T cell responses. Batf3-ko and C57BL/6-mice were infected i.v. with 4 × 106 infectious particles of HSV. Mice were sacrificed 5 days later and spleens were analyzed for presence of HSVgB-specific CD8+ T cells with H-2 Kb/gB498-505-tetramers (top panel) or byex vivo restimulation with gB498-505 peptide and subsequent intracellular FACS-analysis for IFNγ-production (lower panel). Dot plots are gated on CD8+ T cells (upper panel) or lymphocytes (lower panel) first (not shown). Data shown as bar graphs are mean ± SEM fromn = 3 mice per group. (**P = 0.0018 as compared to unstimulated control). Open bars represent C57BL/6-wild type mice and filled bars represent Batf3-ko mice. This experiment has been repeated twice with similar outcome.
Figure 3
Figure 3
Cross-presentation deficient CD11c-Rac mice mount reduced CD8 T cell responses to HSVwt, but normal responses to immune evasion-deficient HSVmut. Mice were immunized i.v. with 4 × 106 infectious particles(A,B,C) or graded amounts(D) of HSVwt or HSVmut and 5 days later CD8+ T cells from spleens were analyzed as described in Figure 2. Dot plots are gated on CD8+ T cells [(A,C) upper panel] or all lymphocytes [(A,C) lower panel] (not shown). Data from one out of four experiments with similar results (n = 3 mice per group) are shown as mean ± SEM in bar graphs (a, c; side insets),t-test analysis, a, upper panel: ***P < 0.0001; *P = 0.0284; a, lower panel *P = 0.0243.(B) Pooled data from seven experiments (n = 3 mice per group, totaln = 21) are displayed as percent of control (C57BL/6). The mean of each control group was set to 100% and the data from the CD11c-Rac-groups were calculated relative to the respective control group (***P = 0.0001).(D) Mice were immunized with the indicated amounts of HSVwt or HSVmut. Analyses were performed as described in(A). HSVwt 0.4 × 105, *P = 0.0221; 4 × 105, *P = 0.0223; 40 × 105, *P = 0.0243; One out of two experiments with similar outcome is shown (n = 3 mice per group).
Figure 4
Figure 4
mCMV responses do not depend on cross-presentation. BMDC were infected with mCMVwt, mCMVmut, or mock-infected. DCs were utilized to either stimulate 5 × 104 CFSE-labeled TCR-transgenic gp33-41-specific CD8+ P14 T cells as described in Figure 1B(A). CFSE-profiles of gated CD8+ T cells are shown for the peptide concentration 0.1 ng/ml. Graphs show results of gated divided T cells of one experiment out of two with similar results.(B) Batf3-ko and C57BL/6-mice were infected i.v. with 4 × 106 infectious particles of mCMVwt or mCMVmut. Mice were sacrificed 7 days later and spleens were analyzed for presence of mCMV-specific CD8+ T cells byex vivo restimulation with the indicated mCMV-peptides and subsequent intracellular FACS-analysis for IFNγ-production. Dot plots are gated on lymphocytes first (not shown).(C) Data from(B) shown as bar graphs are mean ± SEM fromn = 3 mice per group. Open bars represent C57BL/6-wild type (wt) mice and filled bars represent Batf3-ko mice. This experiment has been repeated twice with similar outcome.(D) CD11c-Rac- or C57BL/6-mice were infected i.v. with 4 × 106 infectious particles of mCMVwt or mCMVmut. Mice were sacrificed 5 days later and spleens were analyzed for presence of mCMV-specific CD8+ T cells byex vivo restimulation with the indicated mCMV-peptides and subsequent intracellular FACS-analysis for IFNγ-production. Dot plots are gated on lymphocytes first (not shown).(E) Data from(D) shown as bar graphs are mean ± SEM fromn = 3 mice per group. Open bars represent C57BL/6-wt mice, black bars represent Batf3-ko mice, gray bars are non-immunized controls. This experiment has been repeated twice with similar outcome.
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