<i>Mycobacterium tuberculosis</i>-Induced Bronchoalveolar Lavage Gene Expression Signature in Latent Tuberculosis Infection Is Dominated by Pleiotropic Effects of CD4⁺ T Cell-Dependent IFN-γ Production despite the Presence of Polyfunctional T Cells within the Airways

Tuberculosis (TB) remains a worldwide public health threat. Development of a more effective vaccination strategy to prevent pulmonary TB, the most common and contagious form of the disease, is a research priority for international TB control. A key to reaching this goal is improved understanding of the mechanisms of local immunity to Mycobacterium tuberculosis , the causative organism of TB. In this study, we evaluated global M. tuberculosis -induced gene expression in airway immune cells obtained by bronchoalveolar lavage (BAL) of individuals with latent TB infection (LTBI) and M. tuberculosis -naive controls. In prior studies, we demonstrated that BAL cells from LTBI individuals display substantial enrichment for M. tuberculosis -responsive CD4 + T cells compared with matched peripheral blood samples. We therefore specifically assessed the impact of the depletion of CD4 + and CD8 + T cells on M. tuberculosis -induced BAL cell gene expression in LTBI. Our studies identified 12 canonical pathways and a 47-gene signature that was both sensitive and specific for the contribution of CD4 + T cells to local recall responses to M. tuberculosis In contrast, depletion of CD8 + cells did not identify any genes that fit our strict criteria for inclusion in this signature. Although BAL CD4 + T cells in LTBI displayed polyfunctionality, the observed gene signature predominantly reflected the impact of IFN-γ production on a wide range of host immune responses. These findings provide a standard for comparison of the efficacy of standard bacillus Calmette-Guérin vaccination as well as novel TB vaccines now in development at impacting the initial response to re-exposure to M. tuberculosis in the human lung.