Autophagy is an immune effector response against a variety of intracellular pathogens, including Mycobacterium tuberculosis. Mycobacteria survive in macrophages by blocking maturation of the phagosome. Induction of autophagy by the T helper 1 (Th1) cytokine IFN-gamma, or amino acid starvation, enables macrophages to overcome the phagosome maturation block and impedes mycobacterial survival. This study investigates the role of T helper 2 (Th2) cytokines Interleukin 4 (IL-4) and Interleukin 13 (IL-13) in autophagy in macrophages and their ability to eliminate intracellular mycobacteria. The Th2 cytokines abrogated autophagy and autophagy-induced transfer of mycobacteria into lysosomal compartments, thus enhancing mycobacterial survival within infected macrophages. In murine and human macrophages, inhibition of starvation-induced autophagy by IL-4 and IL-13 was dependent on Akt signaling, whereas the inhibition of IFN-gamma-induced autophagy was Akt independent and signal transducer and activator of transcription 6 (STAT6) dependent. These findings establish a mechanism through which Th1-Th2 polarization differentially influences the immune control of intracellular pathogens.
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