Combined TLR and CD40 triggering induces potent CD8+ T cell expansion with variable dependence on type I IFN.
Toll-like receptors are important in the activation of innate immunity, and CD40 is a molecule critical for many T and B cell responses. Whereas agonists for either pathway have been used as vaccine adjuvants, we show that a combination of Toll-like receptor (TLR)7 and CD40 agonists synergize to stimulate CD8+ T cell responses 10-20-fold greater than the use of either agonist alone. Antigen-specific CD8+ T cells elicited from combination CD40/TLR7 treatment demonstrated both lytic activities and interferon (IFN)gamma production and an enhanced secondary response to antigenic challenge. Agonists for TLRs 2/6, 3, 4, and 9 also synergized with CD40 stimulation, demonstrating that synergy with the CD40 pathway is a property of TLR-derived stimuli in general. The CD8+ T cell expansion induced by CD40/TLR7 triggering was independent of CD4+ T cells, IFNgamma, and IL-12 but dependent on B7-mediated costimulation and surprisingly on type I IFN. These studies provide the rational basis for the use of TLR and CD40 agonists together as essential adjuvants to optimize vaccines designed to elicit protective or therapeutic immunity.
Ahonen
Cory L
CL
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Doxsee
Christie L
CL
McGurran
Sean M
SM
Riter
Tony R
TR
Wade
William F
WF
Barth
Richard J
RJ
Vasilakos
John P
JP
Noelle
Randolph J
RJ
Kedl
Ross M
RM
D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000187:drug effects*; D007114:Immunization; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000276:immunology; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin; D011956:Receptors, Cell Surface / Q000819:agonists*; D015398:Signal Transduction / Q000276:immunology*; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D014612:Vaccines / Q000276:immunology*
C095471:4-amino-alpha,alpha,2-trimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol; D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051199:Toll-Like Receptor 7; D051193:Toll-Like Receptors; D014612:Vaccines; D007371:Interferon-gamma; D010047:Ovalbumin