Mycobacterium tuberculosis Directs T Helper 2 Cell Differentiation by Inducing Interleukin-1β Production in Dendritic Cells

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), resides and replicates within phagocytes and persists in susceptible hosts by modulating protective innate immune responses. Furthermore, M. tuberculosis promotes T helper 2 (Th2) immune responses by altering the balance of T cell polarizing cytokines in infected cells. However, cytokines that regulate Th2 cell differentiation during TB infection remain unknown. Here we show that IL-1 beta, produced by phagocytes infected by virulent M. tuberculosis strain H37Rv, directs Th2 cell differentiation. In sharp contrast, the vaccine strain bacille Calmette-Guerin as well as RD-1 and ESAT-6 mutants of H37Rv failed to induce IL-1 beta and promote Th2 cell differentiation. Furthermore, ESAT-6 induced IL-1 beta production in dendritic cells (DCs), and CD4(+) T cells co-cultured with infected DCs differentiated into Th2 cells. Taken together, our findings indicate that IL-1 beta induced by RD-1/ESAT-6 plays an important role in the differentiation of Th2 cells, which in turn facilitates progression of TB by inhibiting host protective Th1 responses.