T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis.
Autophagy is a recently recognized immune effector mechanism against intracellular pathogens. The role of autophagy in innate immunity has been well established, but the extent of its regulation by the adaptive immune response is less well understood. The T helper 1 (Th1) cell cytokine IFN-gamma induces autophagy in macrophages to eliminate Mycobacterium tuberculosis. Here, we report that Th2 cytokines affect autophagy in macrophages and their ability to control intracellular M. tuberculosis. IL-4 and IL-13 abrogated autophagy and autophagy-mediated killing of intracellular mycobacteria 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 affects the immune control of intracellular pathogens.
Harris
James
J
Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, University of New Mexico School of Medicine, 915 Camino de Salud NE, Albuquerque, NM 87131, USA.
De Haro
Sergio A
SA
Master
Sharon S
SS
Keane
Joseph
J
Roberts
Esteban A
EA
Delgado
Monica
M
Deretic
Vojo
V
D000818:Animals; D001343:Autophagy / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D018613:Microscopy, Confocal; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology*; D014162:Transfection
D016207:Cytokines; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt