Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses

Abstract

Bacterial lipopeptides (bLPs) are increasingly used as adjuvants to activate cell-mediated immune responses to foreign Ags. To explore mechanisms whereby bLPs adjuvant T cell responses, we stimulated human PBMCs with bLPs. We found that bLPs stimulate T cells to proliferate and produce IFN-γ in an accessory cell-dependent manner and in the absence of exogenous protein Ags. The ability of bLPs to stimulate T cell proliferation was Toll-like receptor 2 dependent and required IL-12, interaction with costimulatory molecules, and MHC proteins. Our data suggest that bLPs adjuvant adaptive Th1 responses by enhancing Ag presentation of endogenous peptides.

Synthetic bacterial lipopeptide analogs facilitate naive CD4+ T cell differentiation and enhance antigen-specific HLA-II-restricted responses

“…4). The appearance of IFN-c-producing T cells here described correlates with the increased frequency of CCR7 -/CD45RA -/CD62L dim T cells in P 3 CSK 4 -conditioned cultures presented above, and suggests that BLpA adjuvants preferentially facilitate the expansion of Th1 cells [19]. Furthermore, these effects critically depend on the position and number of the palmitoyl side chains bound to the cystein residue of the CSK 4 backbone peptide, with P 3 CSK 4 and P 2 CSK 4 analogs being the most powerful adjuvants.…”

“…Finally, we investigated the effect of P 3 CSK 4 on CD4 + T cell responses to two HLA-DR-promiscuous, immunodominant epitopes derived from two common human pathogens: TT 947-967 and hepatitis B surface antigen (HBsAg) [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] [23,24]. A higher frequency of peptidespecific T cells in cultures conditioned by P 3 CSK 4 as compared to CSK 4 was demonstrated by LDA analysis (Fig.…”

“…TT, TT 947-967 and HBsAg [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] peptides, and rIL-2 were provided by Dr. A. Wack (Chiron Vaccines, Siena, Italy). GM-CSF was from R&D Systems (Abingdon, UK).…”

“…Freshly isolated PBL from healthy donors were stimulated in vitro with 3 lg/mL TT 947-967 or HBsAg [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] with BLpA. After 5 days, cell lines were restimulated in limiting dilutions (20 Â 10 3 -2.5 Â 10 3 cells/well) in the presence of autologous irradiated PBMC (2 Â 10 4 cells/well) pulsed with the specific antigenic peptide.…”

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

“…Epitopes of defined mycobacterial lipoproteins (19, 27, 38 kDa) have previously been found to induce MHC-restricted T cell responses (74 -78). Lymphocyte activation was attributed to TCR-mediated recognition of conventional proteins or the facilitated presentation of endogenous ligands by supporting costimulation of APCs (37). In contrast, our open approach using the hydrophobic chloroform methanol extract of M.Tb identified native lipopeptides as potent immunogens for primary human T lymphocytes.…”