MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice

J Clin Invest. 2012 May;122(5):1933-47. doi: 10.1172/JCI40591. Epub 2012 Apr 2.


Tregs expressing the transcription factor Foxp3 suppress self-reactive T cells, prevent autoimmunity, and help contain immune responses to foreign antigens, thereby limiting the potential for inadvertent tissue damage. Mutations in the FOXP3 gene result in Treg deficiency in mice and humans, which leads to the development of a multisystem autoimmune inflammatory disease. The contribution of dysregulated innate immune responses to the pathogenesis of Foxp3 deficiency disease is unknown. In this study, we examined the role of microbial signals in the pathogenesis of Foxp3 deficiency disease by studying Foxp3 mutant mice that had concurrent deficiencies in TLR signaling pathways. Global deficiency of the common TLR adaptor MyD88 offered partial protection from Foxp3 deficiency disease. Specifically, it protected from disease at the environmental interfaces of the skin, lungs, and gut. In contrast, systemic disease, in the form of unrestrained lymphoproliferation, continued unabated. The effect of MyD88 deficiency at environmental interfaces involved the disruption of chemokine gradients that recruit effector T cells and DCs, resulting in their entrapment in secondary lymphoid tissues. These results suggests that Tregs have a key role in maintaining tolerance at host-microbial interfaces by restraining tonic MyD88-dependent proinflammatory signals. Moreover, microbial factors may play a substantial role in the pathogenesis of human autoimmune disease resulting from Treg deficiency.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • Cell Movement
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dendritic Cells / physiology
  • Down-Regulation
  • Female
  • Forkhead Transcription Factors / deficiency*
  • Forkhead Transcription Factors / genetics
  • Humans
  • Immune Tolerance*
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / metabolism
  • Intestine, Small / metabolism
  • Intestine, Small / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / physiology*
  • NF-kappa B / metabolism
  • Pneumonia / immunology
  • Pneumonia / metabolism
  • Skin Diseases / immunology
  • Skin Diseases / metabolism
  • Skin Diseases / pathology
  • Spleen / pathology
  • T-Lymphocytes / physiology
  • Toll-Like Receptors / metabolism


  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Toll-Like Receptors