The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

Reiser, Michael; Wieland, Andreas; Plachter, Bodo; Mertens, Thomas; Greiner, Jochen; Schirmbeck, Reinhold

doi:10.4049/jimmunol.1002512

Cited by 16 publications

(10 citation statements)

References 81 publications

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“…A final aspect that deserves mention is that since IgG-containing immune complexes can potently deliver antigen to both MHC class I and MHC class II antigen presentation pathways in DC, the DC which contains both internalization (Fc γ R) and routing (FcRn) receptors is able to assume the critically central role of a single site for CD4 + and CD8 + T cell docking that allows for optimal priming of both helper and cytotoxic responses; the latter of which depends upon T cell help from CD4 + T cells (Fig. 2) [20–22]. While we have only begun to understand the mechanisms behind IgG-mediated cross-presentation enhancement and how it compares to that of soluble antigen, the exquisite sensitivity demonstrated for this system makes it an attractive target for further study.…”

Section: Discussionmentioning

confidence: 99%

“…Such cross-presentation allows the APC to effectively prime CD8 + T cells to antigens associated with pathogens that target intracellular locales and which need such effector functions for their cytolytic removal. As such, a single APC can simultaneously cross-present antigens via MHC class I to CD8 + T cells and present antigens via MHC class II to CD4 + T cells which provide the T cell help necessary for initiating CD8 + T cell effector responses [20–22]. This elegant system allows for a unique geographic localization of both pathways for optimal efficacy.…”

Section: Introductionmentioning

confidence: 99%

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Cross-presentation of IgG-containing immune complexes

Baker

Räth

Lencer

et al. 2012

Cell. Mol. Life Sci.

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IgG is a molecule that functionally combines facets of both innate and adaptive immunity and therefore bridges both arms of the immune system. On the one hand, IgG is created by adaptive immune cells, but can be generated by B cells independently of T cell help. On the other hand, once secreted, IgG can rapidly deliver antigens into intracellular processing pathways, which enable efficient priming of T cell responses towards epitopes from the cognate antigen initially bound by the IgG. While this process has long been known to participate in CD4+ T cell activation, IgG-mediated delivery of exogenous antigens into a major histocompatibility complex (MHC) class I processing pathway has received less attention. The coordinated engagement of IgG with IgG receptors expressed on the cell-surface (FcγR) and within the endolysosomal system (FcRn) is a highly potent means to deliver antigen into processing pathways that promote cross-presentation of MHC class I and presentation of MHC class II-restricted epitopes within the same dendritic cell. This review focuses on the mechanisms by which IgG-containing immune complexes mediate such cross-presentation and the implications that this understanding has for manipulation of immune-mediated diseases that depend upon or are due to the activities of CD8+ T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cross-presentation of IgG-containing immune complexes

Baker

Räth

Lencer

et al. 2012

Cell. Mol. Life Sci.

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“…In some reports CD4 + T cells (or CD4 + T reg cells) were also shown to influence the immunodominance of CD8 + T‐cell responses, such as during DNA immunization or RSV infection []. In contrast, the absence of CD4 + T cells did not affect the CD8 + T‐cell response hierarchy during influenza virus infection [].…”

Section: Primary Cd8+ T‐cell Responses — Do They Require T‐cell Help?mentioning

confidence: 99%

From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help

2012

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CD8 + T cells play an important role in controlling pathogenic infections and are therefore key players in the immune response. It has been shown that among other factors CD4 + T cells can shape the magnitude as well as the quality of primary and/or secondary CD8 + T-cell responses. However, due to the complexity and the differences among diverse immunization or infection models, the overall requirement, the time points, as well as the specific mechanism(s) of CD4 + T-cell help may differ substantially. Here, we summarize current knowledge about the differential requirement of CD4 + T-cell help in promoting primary CD8 + T-cell responses as well as establishing functional memory CD8 + T cells in various experimental settings. Keywords: CD8 + T cells r Differentiation r Memory r T-cell help CD8 + T-cell responsesA number of different parameters influence, by virtue of their strength and composition, CD8 + T-cell activation; they subsequently also shape the size and the phenotypical and functional properties of the resultant memory CD8 + T-cell pool. These parameters include antigen-specific T-cell precursor frequencies [1], the strength of the T-cell receptor interaction with peptide-MHC complexes, and the signals provided by co-stimulatory receptors, as well as innate immune system derived inflammatory cytokines [2,3]. Among the factors that modulate the activation of dendritic cells (DCs), the cells that are the main inducers of CD8 + T-cell responses, is the help provided by CD4 + T cells. CD4 + T-cell engagement of DCs promotes the upregulation of certain costimulatory molecules (such as CD80 and CD86) on, as well as the release of pro-inflammatory cytokines such as IL-12 by, DCs. Thus, in many defined experimental settings, T helper cells have been implicated in the expansion and survival of CD8 + T cells during the primary response, and have a key role in establishing long-lived, functionally robust memory CD8 + T-cell responses [4][5][6][7]. The concept of T-cell help for CD8 + T-cell responses was Correspondence: Prof. Annette Oxenius e-mail: oxenius@micro.biol.ethz.ch further supported by the finding that chemokines secreted by activated CD4 + T helper cells can play a key role in the recruitment of naïve antigen-specific CD8 + T cells to antigen-bearing antigen presenting cells (APCs) in secondary lymphoid organs [8] or to sites of infection [9]. Moreover, in some experimental settings CD4 + T cells were proposed to directly interact with CD8 + T cells, thereby promoting their activation and expansion [10]. Hence, the overall contribution, as well as the mechanism, of helper CD4 + T cells in the initiation of primary and secondary CD8 + T-cell responses is more complex than initially believed and appears to strongly depend on the specific biology of the immunization/infection system.

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“…Immunodominant responses have been observed to a range of pathogens including hepatitis B virus [5,6], Epstein Barr virus (EBV) [7,8], and cytomegalovirus (CMV) [9,10]. As analysis of antiviral T-cell responses for humans is complicated by co-expression of multiple class I alleles, a series of single HLA transgenic (HLA hyb Tg) mice were generated [11,12].…”

Section: Introductionmentioning

confidence: 99%

Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

Akram

Inman

2013

Eur J Immunol

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It is recognized that host response following viral infection is characterized by immunodominance, but deciphering the different factors contributing to immunodominance has proved a challenge due to concurrent expression of multiple MHC class I alleles. To address this, we generated H2-K −/− /D −/− double-knockout transgenic mice expressing either one or two human MHC-I alleles. We hypothesized that co-expression of different allele combinations figures critically in immunodominance and examined this in influenza-infected, double Tg MHC-I mice. In A2/B7 or A2/B27 mice, using ELISpot assays with the A2-restricted matrix I.58-66, the B7-restricted NP418-426 or the B27-restricted NP383-391 influenza A (flu) epitopes, we observed the expected recognition of both peptides for both alleles. In contrast, in flu-infected B7/B27 mice, a significantly reduced level of B27/NP383-restricted CTL response was detected while there was no change in the B7/NP418-restricted CTL response. Flu-specific tetramer studies revealed a partial deletion of Vβ8.1 + NP383/B27-restricted CD8 + T cells, and a diminished Vβ12 + CD8 + T-cell expansion in B7/B27 Tg mice. Using HLA Tg chimeric mice, we confirmed these findings. These findings shed light on the immune consequences of co-dominant expression of MHC-I alleles for host immune response to pathogens.Keywords: HLA-B7 and HLA-B27 r Immunodominance r Influenza A r Thymic selection Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe cellular immune response to a viral infection depends on the ability of CTLs to recognize, via their TCR, viral antigenic peptides in the context of major histocompatibility complex class I molecules (MHC-I) [1]. Following a viral infection, viral peptides are bound by MHC class I molecules and transported to the cell Correspondence: Dr. Robert D. Inman e-mail: robert.inman@uhn.ca surface where they are surveyed for recognition by the repertoire of αβ-TCR expressed by CTLs [2]. In this context, immunodominance refers to the phenomenon whereby a large fraction of the antiviral CTL population is directed against a limited number of MHC class I/peptide complexes (i.e. pMHC-I). The viral peptide that dominates CTL recognition with a particular MHC allele is referred to as the immunodominant (ImD) epitope. As we recently reviewed [3], the mechanisms of immunodominance are not completely understood, but almost every step in antigen processing and presentation may contribute to determine which specific peptide sequences will be available for recognition by CTLs [4].C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3254-3267 Immunity to infection 3255Immunodominance is very common in host response to viral pathogens. Immunodominant responses have been observed to a range of pathogens including hepatitis B virus [5,6], Epstein Barr virus (EBV) [7,8], and cytomegalovirus (CMV) [9,10]. As analysis of antiviral T-cell responses for humans is complica...

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The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

Cited by 16 publications

References 81 publications

Cross-presentation of IgG-containing immune complexes

Cross-presentation of IgG-containing immune complexes

From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help

Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

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The Immunodominant CD8 T Cell Response to the Human Cytomegalovirus Tegument Phosphoprotein pp65495–503 Epitope Critically Depends on CD4 T Cell Help in Vaccinated HLA-A*0201 Transgenic Mice

Cited by 16 publications

References 81 publications

Cross-presentation of IgG-containing immune complexes

Cross-presentation of IgG-containing immune complexes

From crucial to negligible: Functional CD8+T‐cell responses and their dependence on CD4+T‐cell help

Co‐expression of HLA‐B7 and HLA‐B27 alleles is associated with B7‐restricted immunodominant responses following influenza infection

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From crucial to negligible: Functional CD8⁺T‐cell responses and their dependence on CD4⁺T‐cell help