Enhancing CD4+ T cell function as a strategy for improving antibiotic therapy of Mycobacterium tuberculosis infection

In order to develop appropriate combined immuno/chemotherapeutic interventions to treat Mtb infection, it is important to understand the interaction between the host immune response and antibiotic therapy of this pathogen. We and others have observed that CD4 T+ cell responses to Mtb decline after conventional chemotherapy. In an attempt to sustain CD4 + T cell responsiveness during antibiotic treatment, we repeatedly immunized mice with the immunodominant peptides (ESAT-6 4-17 or Ag85B 280-294 ) from the major Mtb antigens ESAT-6 and Ag85B beginning at the start of drug treatment 28days post aerosol infection. When bacillary loads were assayed after 4 weeks of treatment, we found that peptide administration failed to enhance the bacterial clearance observed with chemotherapy alone. Similarly, weekly adoptive transfer of in vitro differentiated Th1 cells specific for ESAT-6 (C7) or Ag85B (P25) during antibiotic treatment failed to improve bacterial clearance despite the successful migration and proliferation of these cells in the lung parenchyma. These findings suggest that therapeutic vaccination by boosting CD4 + T cell responses during the initial phase of Mtb chemotherapy is unlikely to improve the efficacy of treatment. Nevertheless, additional experiments have suggested a major role for endogenous T lymphocytes in drug-mediated control of Mtb infection. Thus, we have observed that antibiotic treatment is ineffective in T cell deficient (TCRα −/− ) mice that have received higher dose infections. We are currently evaluating the nature of this T cell requirement and whether it can be targeted to improve the outcome of Mtb therapy. This work was supported by the intramural research program of the NIAID.