Endogenous dendritic cell subset cDC1 mediates DC vaccine immunity against gamma herpesvirus in syngeneic BMT recipients

Abstract

Abstract Dendritic cell (DC) vaccines are a promising immunotherapy for viral infections and cancers, however the mechanisms underlying their action are still not clear. The objective of this study is to understand how DC vaccines stimulate the expansion of cytotoxic T lymphocytes (CTLs) against gamma herpesvirus in bone marrow transplant (BMT) recipients. Herpesviruses commonly reactivate after transplantation of hematopoietic cells in patients and cause high mortality and morbidity. Similarly, infections with murine gamma herpesvirus 68 (MHV-68), a mouse homolog of Epstein-Barr virus, after syngeneic BMT in mice cause severe pulmonary fibrosis and pneumonitis. We prepared DC vaccines by sorting CD11c+ cells from the lungs at 3 days post infection (dpi) with MHV-68. We administered DC vaccines i.v. to BMT mice one day before infection with MHV-68. CTLs of the lung, spleen and mediastinal draining lymph nodes were analyzed by flow cytometry at 7 dpi. Lung sections were prepared at 21 dpi for histology analysis. Adoptive transfer of the DC vaccine stimulates the expansion of viral specific CD8 T cells in MHV-68 infected syn-BMT mice at 7 dpi, and protects them from pneumonitis and fibrosis at 21 dpi. Surprisingly, none of the transferred conventional DC (cDC) subsets, nor migration into draining lymph nodes, nor MHC class I or class II molecule expression are essential for the DC vaccine to activate CD8 T cells in BMT mice. Instead, DC vaccination of BMT mice lacking endogenous cDC1s resulted in reduced CD8 T cells and failed to suppress lytic viral infection. Our results suggest that endogenous cDC1s in BMT mice mediate DC vaccine immunity against gamma herpesvirus. We have thus revealed a previously unknown pathway of DC vaccination.