Dataset Information

Dynamics of antigen presentation to transgene product-specific CD4⁺ T cells and of Treg induction upon hepatic AAV gene transfer.

ABSTRACT: The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation to transgene product-specific CD4⁺ T cells remains limited. To address this, we administered hepatotropic adeno-associated virus (AAV8) vector expressing cytoplasmic ovalbumin (OVA) into wt mice followed by adoptive transfer of transgenic OVA-specific T cells. We find that that the liver-draining lymph nodes (celiac and portal) are the major sites of MHC II presentation of the virally encoded antigen, as judged by in vivo proliferation of DO11.10 CD4⁺ T cells (requiring professional antigen-presenting cells, e.g., macrophages) and CD4⁺CD25⁺FoxP3⁺ Treg induction. Antigen presentation in the liver itself contributes to activation of CD4⁺ T cells egressing from the liver. Hepatic-induced Treg rapidly disseminate through the systemic circulation. By contrast, a secreted OVA transgene product is presented in multiple organs, and OVA-specific Treg emerge in both the thymus and periphery. In summary, liver draining lymph nodes play an integral role in hepatic antigen presentation and peripheral Treg induction, which results in systemic regulation of the response to viral gene products.

SUBMITTER: Perrin GQ

PROVIDER: S-EPMC5142511 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Dynamics of antigen presentation to transgene product-specific CD4<sup>+</sup> T cells and of Treg induction upon hepatic AAV gene transfer.

Perrin George Q GQ Zolotukhin Irene I Sherman Alexandra A Biswas Moanaro M de Jong Ype P YP Terhorst Cox C Davidoff Andrew M AM Herzog Roland W RW

Molecular therapy. Methods & clinical development 20161207

The tolerogenic hepatic microenvironment impedes clearance of viral infections but is an advantage in viral vector gene transfer, which often results in immune tolerance induction to transgene products. Although the underlying tolerance mechanism has been extensively studied, our understanding of antigen presentation to transgene product-specific CD4<sup>+</sup> T cells remains limited. To address this, we administered hepatotropic adeno-associated virus (AAV8) vector expressing cytoplasmic oval ...[more]

PMID: 27933310

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Project description:While liver inflammation is associated with AIDS, little is known so far about hepatic CD4+ T cells. By using the simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) model, we aimed to characterize CD4+ T cells. The phenotype of CD4+ T cells was assessed by flow cytometry from uninfected (n = 3) and infected RMs, with either SIVmac251 (n = 6) or SHIVSF162p3 (n = 6). After cell sorting of hepatic CD4+ T cells, viral DNA quantification and RNA sequencing were performed.Thus, we demonstrated that liver CD4+ T cells strongly expressed the SIV coreceptor, CCR5. We showed that viremia was negatively correlated with the percentage of hepatic effector memory CD4+ T cells. Consistent with viral sensing, inflammatory and interferon gene transcripts were increased. We also highlighted the presence of harmful CD4+ T cells expressing GZMA and members of TGFB that could contribute to fuel inflammation and fibrosis. Whereas RNA sequencing demonstrated activated CD4+ T cells displaying higher levels of mitoribosome and membrane lipid synthesis transcripts, few genes were related to glycolysis and oxidative phosphorylation, which are essential to sustain activated T cells. Furthermore, we observed lower levels of mitochondrial DNA and higher levels of genes associated with damaged organelles (reticulophagy and mitophagy). Altogether, our data revealed that activated hepatic CD4+ T cells are reprogrammed to lipid metabolism. Thus, strategies aiming to reprogram T cell metabolism with effector function could be of interest for controlling viral infection and preventing liver disorders.IMPORTANCEHuman immunodeficiency virus (HIV) infection may cause liver diseases, associated with inflammation and tissue injury, contributing to comorbidity in people living with HIV. Paradoxically, the contribution of hepatic CD4+ T cells remains largely underestimated. Herein, we used the model of simian immunodeficiency virus (SIV)-infected rhesus macaques to access liver tissue. Our work demonstrates that hepatic CD4+ T cells express CCR5, the main viral coreceptor, and are infected. Viral infection is associated with the presence of inflamed and activated hepatic CD4+ T cells expressing cytotoxic molecules. Furthermore, hepatic CD4+ T cells are reprogrammed toward lipid metabolism after SIV infection. Altogether, our findings shed new light on hepatic CD4+ T cell profile that could contribute to liver injury following viral infection.

Dataset Information

Dynamics of antigen presentation to transgene product-specific CD4⁺ T cells and of Treg induction upon hepatic AAV gene transfer.

Publications

Dynamics of antigen presentation to transgene product-specific CD4<sup>+</sup> T cells and of Treg induction upon hepatic AAV gene transfer.

Similar Datasets

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Dataset Information

Dynamics of antigen presentation to transgene product-specific CD4+ T cells and of Treg induction upon hepatic AAV gene transfer.

Publications

Dynamics of antigen presentation to transgene product-specific CD4<sup>+</sup> T cells and of Treg induction upon hepatic AAV gene transfer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dynamics of antigen presentation to transgene product-specific CD4⁺ T cells and of Treg induction upon hepatic AAV gene transfer.