Extending the CD4(+) T-cell epitope specificity of the Th1 immune responseto an antigen using a Salmonella enterica serovar Typhimurium delivery vehicle

We analyzed the CD4 T-cell immunodominance of the response to a model antig en (Ag), MalE, when delivered by an attenuated strain of Salmonella enteric a serovar Typhimurium (SL3261*pMalE). Compared to purified MalE Ag administ ered with adjuvant, the mapping of the peptide-specific proliferative respo nses showed qualitative differences when we used the Salmonella vehicle. We observed the disappearance of one out of eight MalE peptides' T-cell react ivity upon SL3261*pMalE immunization, but this phenomenon was probably due to a low level of T-cell priming, since it could be overcome by further imm unization. The most striking effect of SL3261*pMalE administration was the activation and stimulation of new MalE peptide-specific T-cell responses th at were silent after administration of purified rig with adjuvant. Ag prese ntation assays performed with MalE-specific T-cell hybridomas showed that i nfection of Ag-presenting cells by this intracellular attenuated bacterium did not affect the processing and presentation of the different MalE peptid es by major histocompatibility complex (MHC) class II molecules and therefo re did not account for immunodominance modulation. Thus. immunodominance of the T-cell response to microorganisms is governed not only by the frequenc y of the available T-cell repertoire or the processing steps in Ag-presenti ng cells that lead to MHC presentation but also by other parameters probabl y related to the infectious process and to the bacterial products. Our resu lts indicate that, upon infection by a microorganism, the specificity of th e T-cell response induced against its Ags can be much more effective than w ith purified Ags and that it cannot completely be mimicked by purified Ags administered with adjuvant.