The multiple routes of MHC-I cross-presentation

Ramirez, Maria C.; Sigal, Luis J.

doi:10.1016/j.tim.2004.03.008

Cited by 16 publications

(10 citation statements)

References 25 publications

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“…The distinct intracellular localizations of newly-formed K b -OVA complexes observed in K b WT, Δ7, and ΔY-derived DCs support the emerging concept of multiple pathways of peptide loading of cross-presented antigens [26], [27]. In our study, the majority of K b WT-OVA complexes were found within early and late endosomal/lysosomal compartments of DCs after exposure to OVA.…”

Section: Discussionsupporting

confidence: 83%

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

et al. 2008

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BackgroundCross-presentation by dendritic cells (DCs) is a crucial prerequisite for effective priming of cytotoxic T-cell responses against bacterial, viral and tumor antigens; however, this antigen presentation pathway remains poorly defined.Methodology/Principal FindingsIn order to develop a comprehensive understanding of this process, we tested the hypothesis that the internalization of MHC class I molecules (MHC-I) from the cell surface is directly involved in cross-presentation pathway and the loading of antigenic peptides. Here we provide the first examination of the internalization of MHC-I in DCs and we demonstrate that the cytoplasmic domain of MHC-I appears to act as an addressin domain to route MHC-I to both endosomal and lysosomal compartments of DCs, where it is demonstrated that loading of peptides derived from exogenously-derived proteins occurs. Furthermore, by chasing MHC-I from the cell surface of normal and transgenic DCs expressing mutant forms of MHC-I, we observe that a tyrosine-based endocytic trafficking motif is required for the constitutive internalization of MHC-I molecules from the cell surface into early endosomes and subsequently deep into lysosomal peptide-loading compartments. Finally, our data support the concept that multiple pathways of peptide loading of cross-presented antigens may exist depending on the chemical nature and size of the antigen requiring processing.Conclusions/SignificanceWe conclude that DCs have ‘hijacked’ and adapted a common vacuolar/endocytic intracellular trafficking pathway to facilitate MHC I access to the endosomal and lysosomal compartments where antigen processing and loading and antigen cross-presentation takes place.

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Section: Discussionsupporting

confidence: 83%

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

et al. 2008

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“…The macrophage plays a variety of roles in the immune defense system, including phagocytosis, tumor cytotoxicity, cytokine secretion and antigen presentation [45], [46], as well as cross-presentation of antigens to naive T cells in vivo [47], [48], [49]. A number of factors are known to “activate” or engage macrophages in these activities, including viral infection.…”

Section: Discussionmentioning

confidence: 99%

IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

et al. 2011

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To evaluate the role of cellular infiltrates in CNS demyelination in immunocompetent mice, we have used a model of multiple sclerosis (MS) in which different strains of mice are infected with a recombinant HSV-1 expressing IL-2. Histologic examination of the mice infected with HSV-IL-2 demonstrates that natural killer cells, dendritic cells, B cells, and CD25 (IL-2rα) do not play any role in the HSV-IL-2-induced demyelination. T cell depletion, T cell knockout and T cell adoptive transfer experiments suggest that both CD8+ and CD4+ T cells contribute to HSV-IL-2-induced CNS demyelination with CD8+ T cells being the primary inducers. In the adoptive transfer studies, all of the transferred T cells irrespective of their CD25 status at the time of transfer were positive for expression of FoxP3 and depletion of FoxP3 blocked CNS demyelination by HSV-IL-2. The expression levels of IL-12p35 relative to IL-12p40 differed in BM-derived macrophages infected with HSV-IL-2 from those infected with wild-type HSV-1. HSV-IL-2-induced demyelination was blocked by injecting HSV-IL-2-infected mice with IL-12p70 DNA. This study demonstrates that suppression of the IL-12p70 function of macrophages by IL-2 causes T cells to become auto-aggressive. Interruption of this immunoregulatory axis results in demyelination of the optic nerve, the spinal cord and the brain by autoreactive T cells in the HSV-IL-2 mouse model of MS.

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“…ϩ T-cell responses against intracellular pathogens and cancer are based on the major histocompatibility complex class I (MHC-I)-restricted presentations of antigenic peptides by professional antigen-presenting cells (APCs) (37). In these specialized immune cells, two classes of MHC-I-restricted antigen presentation pathways exist in parallel that both can be utilized for immunotherapy and vaccination.…”

Section: Accination Strategies For Inducing Cd8mentioning

confidence: 99%

Stable Antigen Is Most Effective for Eliciting CD8⁺T-Cell Responses after DNA Vaccination and Infection with Recombinant Vaccinia VirusIn Vivo

Schliehe

Bitzer

Broek

et al. 2012

J Virol

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The induction of strong CD8+T-cell responses against infectious diseases and cancer has remained a major challenge. Depending on the source of antigen and the infectious agent, priming of CD8+T cells requires direct and/or cross-presentation of antigenic peptides on major histocompatibility complex (MHC) class I molecules by professional antigen-presenting cells (APCs). However, both pathways show distinct preferences concerning antigen stability. Whereas direct presentation was shown to efficiently present peptides derived from rapidly degraded proteins, cross-presentation is dependent on long-lived antigen species. In this report, we analyzed the role of antigen stability on DNA vaccination and recombinant vaccinia virus (VV) infection using altered versions of the same antigen. The long-lived nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) can be targeted for degradation by N-terminal fusion to ubiquitin or, as we show here, to the ubiquitin-like modifier FAT10. Direct presentation by cells either transfected with NP-encoding plasmids or infected with recombinant VVin vitrowas enhanced in the presence of short-lived antigens.In vivo, however, the highest induction of NP-specific CD8+T-cell responses was achieved in the presence of long-lived NP. Our experiments provide evidence that targeting antigens for proteasomal degradation does not improve the immunogenicity of DNA vaccines and recombinant VVs. Rather, it is the long-lived antigen that is superior for the efficient activation of MHC class I-restricted immune responsesin vivo. Hence, our results suggest a dominant role for antigen cross-priming in DNA vaccination and recombinant VV infection.

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The multiple routes of MHC-I cross-presentation

Cited by 16 publications

References 25 publications

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

Stable Antigen Is Most Effective for Eliciting CD8⁺T-Cell Responses after DNA Vaccination and Infection with Recombinant Vaccinia VirusIn Vivo

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The multiple routes of MHC-I cross-presentation

Cited by 16 publications

References 25 publications

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

MHC Class I Endosomal and Lysosomal Trafficking Coincides with Exogenous Antigen Loading in Dendritic Cells

IL-2 Suppression of IL-12p70 by a Recombinant HSV-1 Expressing IL-2 Induces T-Cell Auto-Reactivity and CNS Demyelination

Stable Antigen Is Most Effective for Eliciting CD8+T-Cell Responses after DNA Vaccination and Infection with Recombinant Vaccinia VirusIn Vivo

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Stable Antigen Is Most Effective for Eliciting CD8⁺T-Cell Responses after DNA Vaccination and Infection with Recombinant Vaccinia VirusIn Vivo