OX40 ligand fusion protein delivered simultaneously with the BCG vaccine provides superior protection against murine Mycobacterium tuberculosis infection.
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.
Imperial College, London, UK.
Robert J
RJ
Snelgrove
Megan M
MM
Cornere
Lorna
L
Edwards
Belinda
B
Dagg
James
J
Keeble
Angela
A
Rodgers
Daphne E
DE
Lyonga
Graham R
GR
Stewart
Douglas B
DB
Young
Barry
B
Walker
Tracy
T
Hussell
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001500:BCG Vaccine / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity*; D053278:OX40 Ligand; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology / Q000517:prevention & control*; D048069:Tumor Necrosis Factors / Q000494:pharmacology*; D014611:Vaccination
D001500:BCG Vaccine; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D011993:Recombinant Fusion Proteins; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors