Cross‐priming of CD8<sup>+</sup> T cells by viral and tumor antigens is a robust phenomenon

Chen, Weisan; Masterman, Kelly‐Anne; Basta, Sameh; Haeryfar, S. M. Mansour; Dimopoulos, Nektaria; Knowles, Barbara B.; Bennink, Jack R.; Yewdell, Jonathan W.

doi:10.1002/eji.200324257

Cited by 76 publications

(69 citation statements)

References 17 publications

(19 reference statements)

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“…Furthermore, these findings are consistent with previous results demonstrating that, in the absence of cross-presentation, virus-specific CD8 T cells are impaired (45,46). Additionally it has been demonstrated CD8 T cells generated through cross-presentation are functionally equivalent to those primed by direct presentation (47). Taking these data together, this work explains the lack of phenotype with regards to NP142t pathogenesis and suggests that the overwhelming development of the adaptive response is not mediated by direct presentation.…”

Section: Discussionsupporting

confidence: 92%

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Langlois¹,

Varble²,

Chua³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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A coordinated innate and adaptive immune response, orchestrated by antigen presenting cells (APCs), is required for effective clearance of influenza A virus (IAV). Although IAV primarily infects epithelial cells of the upper respiratory tract, APCs are also susceptible. To determine if virus transcription in these cells is required to generate protective innate and adaptive immune responses, we engineered IAV to be selectively attenuated in cells of hematopoietic origin. Incorporation of hematopoietic-specific miR-142 target sites into the nucleoprotein of IAV effectively silenced virus transcription in APCs, but had no significant impact in lung epithelial cells. Here we demonstrate that inhibiting IAV replication in APCs in vivo did not alter clearance, or the generation of IAV-specific CD8 T cells, suggesting that cross-presentation is sufficient for cytotoxic T lymphocyte activation. In contrast, loss of in vivo virus infection, selectively in APCs, resulted in a significant reduction of retinoic acid-inducible gene I-dependent type I IFN (IFN-I). These data implicate the formation of virus replication intermediates in APCs as the predominant trigger of IFN-I in vivo. Taking these data together, this research describes a unique platform to study the host response to IAV and provides insights into the mechanism of antigen presentation and the induction of IFN-I.

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Section: Discussionsupporting

confidence: 92%

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Langlois¹,

Varble²,

Chua³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Cross-priming is generally accepted as the most important pathway how antigens expressed in parenchymal organs or in tumors induce specific CD8 1 T cells [29][30][31]. However, our earlier experiments using proteins of LCMV as model tumor antigens questioned the relevance of cross-priming in the induction of an anti-tumor immune response and favored the concept that tumor cells in local lymph nodes directly activate specific CTL [2,4,32].…”

Section: Discussionmentioning

confidence: 99%

CTL induction by cross‐priming is restricted to immunodominant epitopes

et al. 2009

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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 Â 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...

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“…Four epitopes derived from the T-Ag have been mapped in B6 mice. T-Ag 404-411 is the most dominant, followed by T-Ag 206-215 (32,38). We administered irradiated D2.…”

Section: Iav Infection Enhanced Cross-priming Of T Cd8+ Response To Cmentioning

confidence: 98%

Influenza A Infection Enhances Cross-Priming of CD8+ T Cells to Cell-Associated Antigens in a TLR7- and Type I IFN-Dependent Fashion

Wei¹,

Waithman²,

Lata³

et al. 2010

The Journal of Immunology

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The initiation of antitumor immunity relies on dendritic cells (DCs) to cross-present cell-associated tumor Ag to CD8+ T cells (TCD8+) due to a lack of costimulatory molecules on tumor cells. Innate danger signals have been demonstrated to enhance cross-priming of TCD8+ to soluble as well as virally encoded Ags; however, their effect on enhancing TCD8+ cross-priming to cell genome-encoded Ags remains unknown. Furthermore, influenza A virus (IAV) has not been shown to enhance antitumor immunity. Using influenza-infected allogeneic cell lines, we show in this study that TCD8+ responses to cell-associated Ags can be dramatically enhanced due to enhanced TCD8+ expansion. This enhanced cross-priming in part involves TLR7- but not TLR3-mediated sensing of IAV and is entirely dependent on MyD88 and IFN signaling pathways. We also showed that the inflammasome-induced IL-1 and IFN-γ did not play a role in enhancing cross-priming in our system. We further demonstrated in our ex vivo system that CD8+ DCs are the only APCs able to prime TCR-transgenic TCD8+. Importantly, plasmacytoid DCs and CD8− DCs were both able to enhance such priming when provided in coculture. These observations suggest that IAV infection of tumor cells may facilitate improved cross-presentation of tumor Ags and may be used to augment clinical vaccine efficacy.

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Cross‐priming of CD8⁺ T cells by viral and tumor antigens is a robust phenomenon

Cited by 76 publications

References 17 publications

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

CTL induction by cross‐priming is restricted to immunodominant epitopes

Influenza A Infection Enhances Cross-Priming of CD8+ T Cells to Cell-Associated Antigens in a TLR7- and Type I IFN-Dependent Fashion

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Cross‐priming of CD8+ T cells by viral and tumor antigens is a robust phenomenon

Cited by 76 publications

References 17 publications

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

CTL induction by cross‐priming is restricted to immunodominant epitopes

Influenza A Infection Enhances Cross-Priming of CD8+ T Cells to Cell-Associated Antigens in a TLR7- and Type I IFN-Dependent Fashion

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Cross‐priming of CD8⁺ T cells by viral and tumor antigens is a robust phenomenon