The role of lipopolysaccharide in the development of specific immunity to Salmonella typhimurium.

摘要

We observed that virulent strains of S. typhimurium, with complete lipopolysaccharide (LPS), did not reactivate T cells from mice immunized with LPS mutant strains. T cell reactivity increased as the LPS length of the bacteria decreased. We hypothesized the polysaccharide portion might be interfering with the T cell response by masking T cell epitopes.; We generated Salmonella specific T cell hybridomas from mice immunized with strains LT2 (wild-type), SL1004 or SA1377 (LPS mutants). Two patterns of hybridoma reactivity were observed: one pattern was equal response, and the other pattern was response to only the LPS mutant strains. This indicated that LPS influenced T cell specificity.; Global suppressive effects of LPS on antigen processing and presentation were investigated. The strains of S. typhimurium were taken up by macrophages equally and did not differentially affect levels of MHC class II expression or IL-12 secretion by macrophages. Over longer antigen processing times, T cell hybridomas that responded poorly to LT2 generated a response equal to that induced by the mutant strains. This indicated the antigens were present in LT2, but were not accessible during early processing.; Because many of the hybridomas responded well to an outer membrane protein (OMP) preparation from the bacteria, we searched the OMP sequences for T cell epitopes. Sequences were analyzed for IEk binding motifs and amphipathic regions. One hybridoma, 25-12, from LT2 immunized mice responded specifically to a sequence from the TraL protein (Amino acids 56–68: WQLIRAAKCGKSS). LPS masking did not effect the T cell hybridoma response to this epitope.; LPS also has strong adjuvant activity. The lipid A portion of LPS readily induced IL-12 from macrophages. IL-12 or LPS when administered with heat killed Listeria monocytogenes enhanced the protective response equal to that of immunization with live Listeria. We found that a detoxified form of LPS, monophosphoryl lipid A (MPL) had adjuvant activity equivalent to LPS and IL-12.; LPS mediates multiple effects on the development of the specific immune response by activation of macrophages for costimulation, MW Class 11 expression and cytokine secretion and by restricting the availability of T cell epitopes. These effects have implications for vaccine development.