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.
Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA.
Cory L
CL
Ahonen
Christie L
CL
Doxsee
Sean M
SM
McGurran
Tony R
TR
Riter
William F
WF
Wade
Richard J
RJ
Barth
John P
JP
Vasilakos
Randolph J
RJ
Noelle
Ross M
RM
Kedl
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