High Frequency of CD4+T Cells Specific for the TB10.4 Protein Correlates with Protection againstMycobacterium tuberculosisInfection

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Abstract
TB10.4 is a newly identified antigen ofMycobacterium tuberculosisrecognized by human and murine T cells upon mycobacterial infection. Here, we show that immunization withMycobacterium bovisBCG induces a strong, genetically controlled, Th1 immune response against TB10.4 in mice. BALB/c and C57BL/6 strains behave as high and low responders to TB10.4 protein, respectively. The TB10.4:74-88 peptide was identified as an immunodominant CD4+T-cell epitope forH-2dmice. Since recent results, as well as the present study, have raised interest in TB10.4 as a subunit vaccine, we analyzed immune responses induced by this antigen delivered by a new vector, the adenylate cyclase (CyaA) ofBordetella pertussis. CyaA is able to target dendritic cells and to deliver CD4+or CD8+T-cell epitopes to the major histocompatibility complex class II/I molecule presentation pathways, triggering specific Th1 or cytotoxic T-lymphocyte (CTL) responses. Several CyaA harboring either the entire TB10.4 protein or various subfragments containing the TB10.4:20-28 CTL epitope were shown to induce TB10.4-specific Th1 CD4+and CD8+T-cell responses. However, none of the recombinant CyaA, injected in the absence of adjuvant, was able to induce protection againstM. tuberculosisinfection. In contrast, TB10.4 protein administered with a cocktail of strong adjuvants that triggered a strong Th1 CD4+T-cell response induced significant protection againstM. tuberculosischallenge. These results confirm the potential value of the TB10.4 protein as a candidate vaccine and show that the presence of high frequencies of CD4+T cells specific to this strong immunogen correlates with protection againstM. tuberculosisinfection.

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