The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online 25 November 2002 doi:10.1084/jem.20020897
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© Rockefeller University Press, 0022-1007/2002/12/1507/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 11, December 2, 2002 1507-1513

Brief Definitive Reports

 Correction of the Iron Overload Defect in ß-2-Microglobulin Knockout Mice by Lactoferrin Abolishes Their Increased Susceptibility to Tuberculosis

Ulrich E. Schaible1, Helen L. Collins1, Friedrich Priem2 and Stefan H.E. Kaufmann1

1 Max-Planck-Institute for Infection Biology, Schumannstr. 21-22
2 Institut für Laboratoriumsmedizin und Pathochemie, Charité, Humboldt-University, Schumannstr. 20-21, D-10117 Berlin, Germany

Address correspondence to U.E. Schaible, Max-Planck-Institute for Infection Biology, Schumannstr. 21-22, D-10117 Berlin, Germany. Phone: 49-30-28460-520; Fax: 49-30-28460-503; E-mail: schaible{at}mpiib-berlin.mpg.de


Abstract
As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. ß-2-microglobulin (ß2m) knockout (KO) mice are more susceptible to tuberculosis than wild-type mice, which is generally taken as a proof for the role of major histocompatibility complex class I (MHC-I)–restricted CD8 T cells in protection against M. tuberculosis. However, ß2m associates with a number of MHC-I–like proteins, including HFE. This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis). Accordingly, ß2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in ß2m–KO mice by lactoferrin treatment significantly reduces the burden of M. tuberculosis to numbers comparable to those observed in MHC class I–KO mice. In parallel, the generation of nitric oxide impaired in ß2m–KO mice was rescued. Conversely, iron overload in the immunocompetent host exacerbated disease. Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria. Our data establish: (a) defective iron metabolism explains the increased susceptibility of ß2m-KO mice over MHC-I–KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.

Key Words: mycobacteria • MHC • innate immunity • macrophages • endosomes


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