Vitamin D is required for IFN-γ-mediated antimicrobial activity of human macrophages

Mario Fabri, Steffen Stenger, Dong Min Shin, Jae Min Yuk, Philip T. Liu, Susan Realegeno, Hye Mi Lee, Stephan R. Krutzik, Mirjam Schenk, Peter A. Sieling, Rosane Teles, Dennis Montoya, Shankar S. Iyer, Heiko Bruns, David M. Lewinsohn, Bruce W. Hollis, Martin Hewison, John S. Adams, Andreas Steinmeyer, Ulrich ZügelGenhong Cheng, Eun Kyeong Jo, Barry R. Bloom, Robert L. Modlin

Research output: Contribution to journalArticle

320 Scopus citations

Abstract

Control of tuberculosis worldwide depends on our understanding of human immune mechanisms, which combat the infection. Acquired T cell responses are critical for host defense against microbial pathogens, yet the mechanisms by which they act in humans remain unclear. We report that T cells, by the release of interferon-γ (IFN-γ), induce autophagy, phagosomal maturation, the production of antimicrobial peptides such as cathelicidin, and antimicrobial activity against Mycobacterium tuberculosis in human macrophages via a vitamin D-dependent pathway. IFN-γ induced the antimicrobial pathway in human macrophages cultured in vitamin D-sufficient sera, but not in sera from African-Americans that have lower amounts of vitamin D and who are more susceptible to tuberculosis. In vitro supplementation of vitamin D-deficient serum with 25-hydroxyvitamin D3 restored IFN-γ-induced antimicrobial peptide expression, autophagy, phagosome-lysosome fusion, and antimicrobial activity. These results suggest a mechanism in which vitamin D is required for acquired immunity to overcome the ability of intracellular pathogens to evade macrophage-mediated antimicrobial responses. The present findings underscore the importance of adequate amounts of vitamin D in all human populations for sustaining both innate and acquired immunity against infection.

Original languageEnglish (US)
JournalScience translational medicine
Volume3
Issue number104
DOIs
StatePublished - Oct 12 2011

ASJC Scopus subject areas

  • Medicine(all)

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    Fabri, M., Stenger, S., Shin, D. M., Yuk, J. M., Liu, P. T., Realegeno, S., Lee, H. M., Krutzik, S. R., Schenk, M., Sieling, P. A., Teles, R., Montoya, D., Iyer, S. S., Bruns, H., Lewinsohn, D. M., Hollis, B. W., Hewison, M., Adams, J. S., Steinmeyer, A., ... Modlin, R. L. (2011). Vitamin D is required for IFN-γ-mediated antimicrobial activity of human macrophages. Science translational medicine, 3(104). https://doi.org/10.1126/scitranslmed.3003045