Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1⁺ macrophages to CD103⁺ dendritic cells

Immunity. 2014 Feb 20;40(2):248-61. doi: 10.1016/j.immuni.2013.12.012. Epub 2014 Jan 23.


Antigen-presenting cells (APCs) in the gut are apt at oral tolerance establishment at steady state and immunity after infection; complex tasks in an environment exposed to the inflammatory burden of the microbiota. Here we show an unanticipated division of labor among APCs for the establishment of oral tolerance. Chemokine receptor CX3CR1(+) macrophages were found to take up soluble fed antigens and quickly transfer them to CD103(+) dendritic cells (DCs). Antigen transfer occurred via a mechanism that was Connexin 43-dependent and required membrane transfer, indicating a physiological role of gap junctions in antigen presentation. Deletion of Connexin 43 in APCs affected antigen transfer and resulted in the inability of CD103(+) DCs to acquire and present antigens in vivo, to drive T regulatory cell differentiation and to induce tolerance to food antigens. This functional cooperation between intestinal phagocytes might be a mechanism to avoid the exposure of tolerogenic DCs to the intestinal microbiota.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology*
  • Antigens, CD / metabolism*
  • CX3C Chemokine Receptor 1
  • Cells, Cultured
  • Dendritic Cells* / metabolism
  • Flow Cytometry
  • Food Hypersensitivity / immunology*
  • Gap Junctions / immunology*
  • Immune Tolerance*
  • Integrin alpha Chains / metabolism*
  • Intestinal Mucosa / immunology
  • Macrophages / immunology*
  • Mice
  • Models, Biological
  • Receptors, Chemokine / metabolism*
  • Solubility


  • Antigens
  • Antigens, CD
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Integrin alpha Chains
  • Receptors, Chemokine
  • alpha E integrins