Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression.
The lethal outcome of high-dose pulmonary virus infection is thought to reflect high-level, sustained virus replication and associated lung inflammation prior to development of an adaptive immune response. Herein, we demonstrate that the outcome of lethal/sublethal influenza infection instead correlates with the initial virus replication tempo. Furthermore, the magnitude of early lung antiviral CD8+ T cell responses varies inversely with inoculum dose and is controlled by lymph-node-resident dendritic cells (LNDC) through IL-12p40-regulated FasL-dependent T cell apoptosis. These results suggest that the inoculum dose and replication rate of a pathogen entering the respiratory tract may regulate the strength of the adaptive immune response, and the subsequent outcome of infection and that LNDC may serve as regulators (gatekeepers) in the development of CD8+ T cell responses.
Legge
Kevin L
KL
Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Braciale
Thomas J
TJ
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D008168:Lung / Q000821:virology; D008198:Lymph Nodes / Q000166:cytology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D048069:Tumor Necrosis Factors / Q000378:metabolism*; D014779:Virus Replication / Q000276:immunology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors