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In vivo gene delivery to lymph node stromal cells leads to transgene-specific CD8+ T cell anergy in mice.

In vivo gene delivery to lymph node stromal cells leads to transgene-specific CD8+ T cell anergy in mice.
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Ciré S, Da Rocha S, Ferrand M, Collins MK, Galy A,


Ciré S, Da Rocha S, Ferrand M, Collins MK, Galy A, (click to view)

Ciré S, Da Rocha S, Ferrand M, Collins MK, Galy A,

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Molecular therapy : the journal of the American Society of Gene Therapy 2016 8 26() doi 10.1038/mt.2016.168

Abstract

Lymph node stromal cells play a role in self-tolerance by presenting tissue antigens to T cells. Yet, immunomodulatory properties of lymphoid tissue stroma, paticularly towards CD4+ T cells, remain insufficiently characterized by lack of tools to target antigens for presentation by stromal cells. A lentiviral vector was therefore designed for antigen delivery to MHC class II(+)cells of non-hematopoietic origin. Following intravenous vector delivery, the transgene was detected in lymph node gp38+ stromal cells which were CD45- MHCII+ and partly positive for CD86 and CTLA4 or B7-H4. The transgene was not detected in classical dendritic cells of lymph nodes or spleen. Transgene-specific CD4+ and CD8+ T cell responses were primed and regulatory T cells were also induced but effector T cell response did not develop, even after a peptide boost. Antigen-specific CD8+ T cells were not cytolytic in vivo. Thus, expressing a neo-antigen in MHC-II+ lymph node stroma seems to trigger blunt CD4 T cell responses leading to antigen-specific CD8+ T cell anergy. These results open up new perspectives to further characterize lymph node stromal cell functional properties and to develop gene transfer protocols targeting lymph node stroma to induce peripheral tolerance.

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