ABSTRACT
Mycobacterium tuberculosis infection claims approximately 2 million lives per year, and improved efficacy of the BCG vaccine remains a World Health Organization priority. Successful vaccination against M. tuberculosis requires the induction and maintenance of T cells. Targeting molecules that promote T-cell survival may therefore provide an alternative strategy to classic adjuvants. We show that the interaction between T-cell-expressed OX40 and OX40L on antigen-presenting cells is critical for effective immunity to BCG. However, because OX40L is lost rapidly from antigen-presenting cells following BCG vaccination, maintenance of OX40-expressing vaccine-activated T cells may not be optimal. Delivering an OX40L:Ig fusion protein simultaneously with BCG provided superior immunity to intravenous and aerosol M. tuberculosis challenge even 6 months after vaccination, an effect that depends on natural killer 1.1(+) cells. Attenuated vaccines may therefore lack sufficient innate stimulation to maintain vaccine-specific T cells, which can be replaced by reagents binding inducible T-cell costimulators.
Subject(s)
BCG Vaccine/immunology , Membrane Glycoproteins/pharmacology , Mycobacterium tuberculosis/pathogenicity , Tuberculosis/prevention & control , Tumor Necrosis Factors/pharmacology , Vaccination , Animals , Antigen-Presenting Cells/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cell Proliferation , Female , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/immunology , OX40 Ligand , Recombinant Fusion Proteins/pharmacology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , Th1 Cells/drug effects , Th1 Cells/metabolism , Tuberculosis/immunologyABSTRACT
The lung must maintain a high threshold of immune 'ignorance' to innocuous antigens to avoid inflammatory disease that depends on the balance of positive inflammatory signals and repressor pathways. We demonstrate here that airway macrophages had higher expression of the negative regulator CD200 receptor (CD200R) than did their systemic counterparts. Lung macrophages were restrained by CD200 expressed on airway epithelium. Mice lacking CD200 had more macrophage activity and enhanced sensitivity to influenza infection, which led to delayed resolution of inflammation and, ultimately, death. The administration of agonists that bind CD200R, however, prevented inflammatory lung disease. Thus, CD200R is critical for lung macrophage immune homeostasis in the resting state and limits inflammatory amplitude and duration during pulmonary influenza infection.
