Journal
JOURNAL OF IMMUNOLOGY
Volume 190, Issue 8, Pages 4196-4204Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202688
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Funding
- National Institutes of Health [R01 AI085669, AI098637, R01 AI072143, R01 AI 073774, P30 AI060354]
- T Cell-Immunoglobulin and Mucin-Domain-Containing Molecule program project [P01 AI 073748]
- American Lung Association [RT-123085-N]
- Harvard University Center for AIDS Research Scholar Award
- National Institute of Allergy and Infectious Diseases
- National Cancer Institute
- National Institute of Child Health and Human Development
- National Heart, Lung, and Blood Institute
- National Institute on Drug Abuse
- National Institute of Mental Health
- National Institute on Aging
- National Center for Complementary and Alternative Medicine
- Fogarty International Center
- Office of AIDS Research
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In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effector Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to downregulate Th1 responses, we recently described that its interaction with Galectin-9 expressed by M. tuberculosis-infected macrophages stimulates IL-1 beta secretion, which is essential for survival in the mouse model. Why IL-1 beta is required for host resistance to M. tuberculosis infection is unknown. In this article, we show that IL-1 beta directly kills M. tuberculosis in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1 beta directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1 beta and downstream TNF production lead to caspase-dependent restriction of intracellular M. tuberculosis growth. The Journal of Immunology, 2013, 190: 4196-4204.
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