Oral tolerance can be established via gap junction transfer of fed antigens from CX3CR1⁺ macrophages to CD103⁺ dendritic cells.
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.
Department of Experimental Oncology, European Institute of Oncology, I-20139 Milan, Italy.
Elisa
E
Mazzini
Department of Experimental Oncology, European Institute of Oncology, I-20139 Milan, Italy.
Lucia
L
Massimiliano
Department of Experimental Oncology, European Institute of Oncology, I-20139 Milan, Italy.
Giuseppe
G
Penna
Department of Experimental Oncology, European Institute of Oncology, I-20139 Milan, Italy. Electronic address: maria.rescigno@ieo.eu.
Maria
M
Rescigno
D000818:Animals; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism; D005434:Flow Cytometry; D005512:Food Hypersensitivity / Q000276:immunology*; D017629:Gap Junctions / Q000276:immunology*; D007108:Immune Tolerance; D039001:Integrin alpha Chains / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008954:Models, Biological; D019707:Receptors, Chemokine / Q000378:metabolism*; D012995:Solubility
D000941:Antigens; D015703:Antigens, CD; D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D039001:Integrin alpha Chains; D019707:Receptors, Chemokine; C091367:alpha E integrins