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-specific T-cell responses as well as tolerance induction. Using the recall antigen tetanus toxoid for primary in vitro T-cell stimulation, we observed that LPS synergized with peptides to augment proliferation, particularly when used 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 clear enhancement of in vitro peptide-specific responses we then tested whether LPS could influence antigen-specific tolerance driven by coincubation of antigen (tetanus toxoid; TT or immunodominant peptides) with human CTLA-4Ig fusion protein. As expected, CTLA-4Ig treatment inhibited responses to peptides. LPS (100 pg/ml) induced a partial recovery of primary in vitro proliferation under these conditions and the presence of LPS during the primary stimulation prevented the induction of tolerance normally observed on re-stimulation with the same antigen alone. Contrary to the synergistic effects 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-stimulation with peptide. LPS could therefore exert dramatic effects on antigen-specific proliferation and CTLA-4Ig-induced non-responsiveness in human T cells, although via distinct mechanisms. These results reinforce the evidence that LPS influences T-cell function, most likely as a consequence of myeloid cell activation.
Goodier
M R
MR
Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, 1 Aspenlea Road, London W6 8LH, UK.
Londei
M
M
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology*; D060908:CTLA-4 Antigen; D018929:Cell Culture Techniques; D004306:Dose-Response Relationship, Immunologic; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D010455:Peptides; D011993:Recombinant Fusion Proteins; D013745:Tetanus Toxoid; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000069594:Abatacept