Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis

J Exp Med. 2002 Dec 2;196(11):1507-13. doi: 10.1084/jem.20020897.


As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. beta-2-microglobulin (beta2m) 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, beta2m 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, beta2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in beta2m-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 beta2m-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 beta2m-KO mice over MHC-I-KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.

MeSH terms

  • Animals
  • Disease Susceptibility
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / physiology
  • Interferon-gamma / pharmacology
  • Iron Overload / drug therapy*
  • Iron Overload / immunology
  • Lactoferrin / therapeutic use*
  • Macrophages / microbiology
  • Macrophages / physiology
  • Membrane Proteins / physiology
  • Mice
  • Mice, Knockout
  • Mycobacterium tuberculosis / growth & development
  • Nitric Oxide / biosynthesis
  • Receptors, Transferrin / analysis
  • Tuberculosis / immunology*
  • beta 2-Microglobulin / physiology*


  • Hemochromatosis Protein
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • Receptors, Transferrin
  • beta 2-Microglobulin
  • Nitric Oxide
  • Interferon-gamma
  • Lactoferrin