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Activation of different pattern recognition receptors causes distinct profiles of innate immune responses, which in turn dictate the adaptive immune response. We found that mice had higher CD4 +  T cell expansion to an immunogen, ovalbumin, when coadministered with CpG than with CL097  in vivo . To account for this differential adjuvanticity, we assessed the activities of CpG and CL097 on antigen-specific CD4 +  T cell expansion  in vitro  using an OT-II CD4 +  T cell/bone marrow-derived dendritic cell (DC) co-culture system. Unexpectedly, ovalbumin-stimulated expansion of OT-II CD4 +  T cells  in vitro  was potently suppressed by both TLR agonists, with CL097 being stronger than CpG. The suppression was synergistically reversed by co-inhibition of cyclooxygenases 1 and 2, and inducible nitric oxide (NO) synthase. In addition, stimulation of OT-II CD4 +  T cell/DC cultures with CL097 induced higher levels of CD4 +  T cell death than stimulation with CpG, and this CD4 +  T cell turnover was reversed by NO and PGE 2  inhibition. Consistently, the co-cultures stimulated with CL097 produced higher levels of prostaglandin E 2  (PGE 2 ) and NO than stimulation with CpG. CL097 induced higher PGE 2  production in DC cultures and higher IFN-γ in the OT-II CD4 +  T cell/DC cultures, accounting for the high levels of PGE 2  and NO. This study demonstrates that the adjuvant activities of immunostimulatory molecules may be determined by differential induction of negative regulators, including NO and PGE 2  suppressing clonal expansion and promoting cell death of CD4 +  T cells.

Differential Adjuvant Activities of TLR7 and TLR9 Agonists Inversely Correlate with Nitric Oxide and PGE2 Production