Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists

Kamgang, Richard Kenmoe; Ramos, Inês; Rodrigues Duarte, Lurdes; Ghielmetti, Mascia; Freudenberg, Marina; Dahinden, Clemens; Padovan, Elisabetta (2008). Using distinct molecular signatures of human monocytes and dendritic cells to predict adjuvant activity and pyrogenicity of TLR agonists. Medical microbiology and immunology, 197(4), pp. 369-79. Berlin: Springer 10.1007/s00430-008-0081-6

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We present a systematic study that defines molecular profiles of adjuvanticity and pyrogenicity induced by agonists of human Toll-like receptor molecules in vitro. Using P(3)CSK(4), Lipid A and Poly I:C as model adjuvants we show that all three molecules enhance the expansion of IFNgamma(+)/CD4(+) T cells from their naïve precursors following priming with allogeneic DC in vitro. In contrast, co-culture of naive CD4(+) T cells with allogeneic monocytes and TLR2/TLR4 agonists only resulted in enhanced T cell proliferation. Distinct APC molecular signatures in response to each TLR agonist underline the dual effect observed on T cell responses. Using protein and gene expression assays, we show that TNF-alpha and CXCL10 represent DC-restricted molecular signatures of TLR2/TLR4 and TLR3 activation, respectively, in sharp contrast to IL-6 produced by monocytes upon stimulation with P(3)CSK(4) and Lipid A. Furthermore, although all TLR agonists are able to up-regulate proIL-1beta specific gene in both cell types, only monocyte activation with Lipid A results in detectable IL-1beta release. These molecular profiles, provide a simple screen to select new immune enhancers of human Th1 responses suitable for clinical application.

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