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Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8⁺ T Cells.

ABSTRACT: Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8⁺ T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic choriomeningitis virus (LCMV), a finding showing that the spleen was not necessary in generating autoimmunity. By contrast, the absence of LNs prevented the priming of LCMV-specific CD8⁺ T cells, and diabetes did not develop in these mice. Additionally, we found that dendritic cells are responsible for the distribution of virus in secondary lymphoid organs, when LCMV was administered intravenously. Preventing this distribution with the sphingosine-1-phosphate receptor antagonist FTY720 inhibits the transport of antigen to peripheral LNs and consequently prevented the onset of diabetes. However, in case of subcutaneous infection, administration of FTY720 could not inhibit the onset of diabetes because the viral antigen is already presented in the peripheral LNs. These findings demonstrate the importance of preventing the presence of antigen in LNs for maintaining tolerance.

SUBMITTER: Honke N

PROVIDER: S-EPMC5301005 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8<sup>+</sup> T Cells.

Honke Nadine N Shaabani Namir N Teijaro John R JR Christen Urs U Hardt Cornelia C Bezgovsek Judith J Lang Philipp A PA Lang Karl S KS

Frontiers in immunology 20170210

Peripheral tolerance is an important mechanism by which the immune system can guarantee a second line of defense against autoreactive T and B cells. One autoimmune disease that is related to a break of peripheral tolerance is diabetes mellitus type 1. Using the RIP-GP mouse model, we analyzed the role of the spleen and lymph nodes (LNs) in priming CD8<sup>+</sup> T cells and breaking peripheral tolerance. We found that diabetes developed in splenectomized mice infected with the lymphocytic chori ...[more]

PMID: 28239381

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Project description:Vaccinia virus (VACV) was the vaccine used to eradicate smallpox and is being repurposed as a vaccine vector. CD8+ T cells are key anti-viral mediators, but require priming to become effector or memory cells. Priming requires an interaction with dendritic cells that are either infected (direct priming), or that have acquired virus proteins but remain uninfected (cross priming). To investigate CD8+ T cell priming pathways for VACV, we engineered the virus to express CPXV12 and CPXV203, two inhibitors of antigen presentation encoded by cowpox virus. These intracellular proteins would be expected to block direct but not cross priming. The inhibitors had diverse impacts on the size of anti-VACV CD8+ T cell responses across epitopes and by different infection routes in mice, superficially suggesting variable use of direct and cross priming. However, when we then tested a form of antigen that requires direct priming, we found surprisingly that CD8+ T cell responses were not diminished by co-expression with CPXV12 and CPXV203. We then directly quantified the impact of CPXV12 and CPXV203 on viral antigen presentation using mass spectrometry, which revealed strong, but incomplete inhibition of antigen presentation by the CPXV proteins. Therefore, direct priming of CD8+ T cells by poxviruses is robust enough to withstand highly potent viral inhibitors of antigen presentation. This is a reminder of the limits of viral immune evasion and shows that viral inhibitors of antigen presentation cannot be assumed to dissect cleanly direct and cross priming of anti-viral CD8+ T cells.ImportanceCD8+ T cells are key to anti-viral immunity, so it is important to understand how they are activated. Many viruses have proteins that protect infected cells from T cell attack by interfering with the process that allows virus infection to be recognised by CD8+ T cells. It is thought that these proteins would also stop infected cells from activating T cells in the first place. However, we show here that this is not the case for two very powerful inhibitory proteins from cowpox virus. This demonstrates the flexibility and robustness of immune processes that turn on the immune responses required to fight infection.

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Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8⁺ T Cells.

Publications

Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8<sup>+</sup> T Cells.

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Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8+ T Cells.

Publications

Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8<sup>+</sup> T Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Presentation of Autoantigen in Peripheral Lymph Nodes Is Sufficient for Priming Autoreactive CD8⁺ T Cells.