RRC ID 67040
Author Cupovic J, Ring SS, Onder L, Colston JM, Lütge M, Cheng HW, De Martin A, Provine NM, Flatz L, Oxenius A, Scandella E, Krebs P, Engeler D, Klenerman P, Ludewig B.
Title Adenovirus vector vaccination reprograms pulmonary fibroblastic niches to support protective inflating memory CD8+ T cells.
Journal Nat Immunol
Abstract Pathogens and vaccines that produce persisting antigens can generate expanded pools of effector memory CD8+ T cells, described as memory inflation. While properties of inflating memory CD8+ T cells have been characterized, the specific cell types and tissue factors responsible for their maintenance remain elusive. Here, we show that clinically applied adenovirus vectors preferentially target fibroblastic stromal cells in cultured human tissues. Moreover, we used cell-type-specific antigen targeting to define critical cells and molecules that sustain long-term antigen presentation and T cell activity after adenovirus vector immunization in mice. While antigen targeting to myeloid cells was insufficient to activate antigen-specific CD8+ T cells, genetic activation of antigen expression in Ccl19-cre-expressing fibroblastic stromal cells induced inflating CD8+ T cells. Local ablation of vector-targeted cells revealed that lung fibroblasts support the protective function and metabolic fitness of inflating memory CD8+ T cells in an interleukin (IL)-33-dependent manner. Collectively, these data define a critical fibroblastic niche that underpins robust protective immunity operating in a clinically important vaccine platform.
Volume 22(8)
Pages 1042-1051
Published 2021-8-1
DOI 10.1038/s41590-021-00969-3
PII 10.1038/s41590-021-00969-3
PMID 34267375
PMC PMC7611414
MeSH Adenoviridae / genetics Adenoviridae / immunology* Animals CD8-Positive T-Lymphocytes / immunology* Cell Line, Tumor Chemokine CCL19 / metabolism Chimera / genetics Epitopes, T-Lymphocyte / immunology Fibroblasts / cytology Fibroblasts / metabolism Genetic Vectors / immunology Humans Immunologic Memory / immunology* Interleukin-33 / immunology* Lung / cytology Lymphocyte Activation / immunology* Melanoma, Experimental / immunology Mice Mice, Inbred C57BL Mice, Knockout Stromal Cells / immunology* Vaccination
IF 20.479
Human and Animal Cells B16 melanoma/lacZ(RCB1284)