We present a systematic study that deWnes molecular proWles 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 IFN + /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 eVect observed on T cell responses. Using protein and gene expression assays, we show that TNF-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-1 speciWc gene in both cell types, only monocyte activation with Lipid A results in detectable IL-1 release. These molecular proWles, provide a simple screen to select new immune enhancers of human Th1 responses suitable for clinical application.
Synthetic di-and tri-palmitoylated bacterial lipopeptide analogs (BLpA) can enhance HLA-I-restricted immune responses. Here we show that BLpA indirectly promote antigen-driven differentiation of naive CD4 + T lymphocytes in vitro, with mechanisms that require DC and are inhibited by CTLA-4/Ig. In mixed cultures of cord blood-derived PBMC and allogeneic DC, P 3 CSK 4 lipopeptide facilitated the transition from CCR7 + / CD45RA + /CD62L + to CCR7 -/CD45RA -/CD62L dim T cells with kinetics significantly exceeding those obtained with the unlipidated CSK 4 analog. Moreover, P 3 CSK 4 and P 2 CSK 4 , but neither the mono-palmitoylated PCSK 4 analog nor the CSK 4 peptide, increased the frequency of IFN-c-producing T cells expanded under similar conditions. Along with this, P 2 CSK 4 and P 3 CSK 4 , but not PCSK 4 , restored the in vitro antigenicity of MDP-OspA, a non-immunogenic analog of Borrelia burgdorferi major outer surface lipoprotein A, and enhanced the frequency of in vitro expanded T cells specific for the tetanus toxoid (TT) and hepatitis B surface antigen (HBsAg) peptides TT 947-967 and HBsAg 19-33 and for TT. Altogether, BLpA bearing at least two ester-bonded palmitoyl side chains indirectly enhance antigen-driven CD4 + T cell differentiation. BLpA adjuvanticity is independent of covalent bonding to Ag and Ag formulation. This information may be helpful to generate more potent recombinant vaccines.
Investigations into the immunogenicity of the prion protein are ongoing. To combat its pathological isoform without affecting the cellular protein is a challenge in prion research. We here summarize the studies in which prion protein peptides have been used for immunization, to thus determine the most immunogenic parts of the prion protein.
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