tb both induced T cells specific for the known epitope residing in TB10.4-P8 27, whereas P3 and P7 were
the main epitopes recognized following TB10.4 vaccination, in agreement with an earlier study (Fig. 1 and 215). Interestingly, although TB10.4 as a subunit vaccine does not induce T cells specific for the major CD4 epitope induced by infection (P8), TB10.4 has been shown to protect CB6F1 mice against an infection with virulent M.tb. This indicates that an M.tb infection does lead to some intracellular processing and presentation of P3 and/or P7 despite the low numbers of infection-driven P3- and P7-specific T cells. It also indicates that vaccines may not have to induce responses against dominant infection-driven T-cell epitopes in order to be protective. This may be important for future vaccine design as discussed below in the concluding remarks of the Discussion Lenvatinib section. It has been demonstrated that post-translational modifications and native folding of Ag can alter immunogenicity
of a protein and even mask or unmask certain epitopes check details in an Ag compared with the recombinant version of the same antigen 29, 30. However, we found that immunization with native TB10.4 did not alter the epitope pattern compared to immunization with recombinant TB10.4 produced in E. coli (Fig. 3). In addition, TB10.4 is believed to be co-transcribed and secreted from both BCG and M.tb in a complex with Rv0287 19, 20. Complex formation of the related Ag CFP10-ESAT-6 has been shown to alter the structure, stability and function of these Ag 31, and to reduce their immunogenicity 32, 33. However, we showed that immunizing
with the native complex TB10.4-Rv0287 induced recognition of the same epitopes recognized after immunization with monomer TB10.4 and induced a similar level of IFN-γ production (Fig. 4). Furthermore, it was shown that boosting BCG with TB10.4 led to recognition of the dominant epitopes induced by both BCG and TB10.4, suggesting Carnitine dehydrogenase that the different epitope patterns after TB10.4 and BCG immunization were not due to mutually exclusive dominance between epitopes. BCG and M.tb encode two TB10.4-homologues, TB10.3 and TB12.9 34. Possibly, BCG or M.tb could induce T cells specific for P8 in TB10.3/TB12.9, and not TB10.4. However, only TB10.4 was predicted by RANKPEP (http://bio.dfci.harvard.edu/RANKPEP) 35 to have an MHC-II (I-Ad)-restricted epitope within P8 for the b and d haplotype-restricted CB6F1 mice, suggesting that the P8-specific CD4+ T cells observed in our study recognized P8 from TB10.4. Both BCG and TB10.4/CAF01 vaccines were taken up by DC and macrophages, but TB10.4/CAF01 was targeted by DC to a higher degree than BCG in line with results from Korsholm et al. 7 (Fig. 4). On the other hand, BCG was taken up efficiently by granulocytic Ly6-G expressing neutrophils, in agreement with a recent study by Abadie et al. 5.
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