Maintenance of pulmonary Th1 effector function in chronic tuberculosis requires persistent IL-12 production.
The mechanisms that prevent reactivation of latent Mycobacterium tuberculosis infection in asymptomatic individuals are poorly understood. Although IL-12 is critical for the induction of IFN-gamma-dependent host control of M. tuberculosis, the requirement for the cytokine in the maintenance of host resistance and pulmonary Th1 effector function has not yet been formally examined. In this study, we reconstituted IL-12p40-deficient mice with IL-12 during the first 4 wk of infection and then assessed the effects of cytokine withdrawal. Although IL-12 administration initially resulted in restricted mycobacterial growth and prolonged survival, the reconstituted animals eventually succumbed to infection. This breakdown in bacterial control was accompanied by a marked reduction in the numbers of IFN-gamma-producing CD4(+) T cells in lungs. Moreover, whereas CD4(+) T cells isolated from chronically infected wild-type mice expanded and transferred long-term protection to M. tuberculosis-challenged RAG(-/-) mice, they failed to do so in IL-12p40-deficient RAG(-/-) recipients and were clearly reduced in frequency within pulmonary granulomas in the latter animals. These studies establish that continuous IL-12 production is necessary for maintenance of the pulmonary Th1 cells required for host control of persistent M. tuberculosis infection and suggest that breakdown of this mechanism could be a contributing factor in reactivated disease.
Feng
Carl G
CG
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-8003, USA. cfeng@niaid.nih.gov
Jankovic
Dragana
D
Kullberg
Marika
M
Cheever
Allen
A
Scanga
Charles A
CA
Hieny
Sara
S
Caspar
Patricia
P
Yap
George S
GS
Sher
Alan
A
D019264:Adoptive Transfer; D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002908:Chronic Disease; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000276:immunology*; D053762:Interleukin-12 Subunit p40; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology; D021122:Protein Subunits / Q000096:biosynthesis* / Q000276:immunology*; D012008:Recurrence; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*
D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma