Low concentrations of lipopolysaccharide synergize with peptides to augment human T-cell proliferation and can prevent the induction of non-responsiveness by CTLA4-Ig

We investigate how lipopolysaccharide (LPS) could influence antigen-specifi c T-cell responses as well as tolerance induction. Using the recall antigen tetanus toroid for primary in vitro T-cell stimulation, we observed that L PS synergized with peptides to augment proliferation, particularly when use d at low concentrations (as little as 100 pg/ml), and that interleukin-12 ( IL-12) was partially required for this synergistic effect. Because of the c lear enhancement of in vitro peptide-specific responses we then tested whet her LPS could influence antigen-specific tolerance driven by coincubation o f antigen (tetanus toroid: TT or immunodominant peptides) with human CTLA-4 Ig fusion protein. As expected. CTLA-4Ig treatment inhibited responses to p eptides. LPS (100 pg/ml) induced a partial recovery of primary in vitro pro liferation under these conditions and the presence of LPS during the primar y stimulation prevented the induction of tolerance normally observed oil re -stimulation with the same antigen alone. Contrary to the synergistic effec ts on peptide proliferation this action was not caused by release of IL-12. In addition, the neutralization of tumour necrosis factor-alpha (TNF-alpha ) during the primary stimulation did not inhibit proliferation on re-stimul ation with peptide. LPS could therefore exert dramatic effects on antigen-s pecific proliferation and CTLA-4Ig-induced non-responsiveness in human T ce lls, although via distinct mechanisms. These results reinforce the evidence that LPS influences T-cell function, most likely as a consequence of myelo id cell activation.