Microbiota control immune regulation in humanized mice

JCI Insight. 2017 Nov 2;2(21):e91709. doi: 10.1172/jci.insight.91709.

Abstract

The microbiome affects development and activity of the immune system, and may modulate immune therapies, but there is little direct information about this control in vivo. We studied how the microbiome affects regulation of human immune cells in humanized mice. When humanized mice were treated with a cocktail of 4 antibiotics, there was an increase in the frequency of effector T cells in the gut wall, circulating levels of IFN-γ, and appearance of anti-nuclear antibodies. Teplizumab, a non-FcR-binding anti-CD3ε antibody, no longer delayed xenograft rejection. An increase in CD8+ central memory cells and IL-10, markers of efficacy of teplizumab, were not induced. IL-10 levels were only decreased when the mice were treated with all 4 but not individual antibiotics. Antibiotic treatment affected CD11b+CD11c+ cells, which produced less IL-10 and IL-27, and showed increased expression of CD86 and activation of T cells when cocultured with T cells and teplizumab. Soluble products in the pellets appeared to be responsible for the reduced IL-27 expression in DCs. Similar changes in IL-10 induction were seen when human peripheral blood mononuclear cells were cultured with human stool samples. We conclude that changes in the microbiome may impact the efficacy of immunosuppressive medications by altering immune regulatory pathways.

Publication types

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

MeSH terms

  • Adaptive Immunity / immunology
  • Animals
  • Antibodies, Antinuclear
  • Antibodies, Monoclonal, Humanized / immunology*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / microbiology
  • B7-2 Antigen / metabolism
  • CD11b Antigen
  • CD11c Antigen
  • CD3 Complex
  • CD8-Positive T-Lymphocytes / immunology
  • Cytokines / blood
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gastrointestinal Microbiome / immunology*
  • Gastrointestinal Microbiome / physiology*
  • Gastrointestinal Tract / immunology*
  • Gastrointestinal Tract / microbiology
  • Graft Rejection / immunology
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunotherapy
  • Interferon-gamma
  • Interleukin-10 / metabolism
  • Interleukin-27 / metabolism
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / metabolism*
  • Mice
  • Mice, Knockout
  • Mucous Membrane / immunology
  • STAT5 Transcription Factor / metabolism
  • Skin Transplantation
  • T-Lymphocytes / immunology
  • Transplantation, Heterologous

Substances

  • Antibodies, Antinuclear
  • Antibodies, Monoclonal, Humanized
  • B7-2 Antigen
  • CD11b Antigen
  • CD11c Antigen
  • CD3 Complex
  • Cd3e protein, mouse
  • Cd86 protein, mouse
  • Cytokines
  • IL10 protein, mouse
  • Immunosuppressive Agents
  • Interleukin-27
  • STAT5 Transcription Factor
  • Interleukin-10
  • Interferon-gamma
  • teplizumab