Pediatric tolerogenic DCs expressing CD4 and immunoglobulin‐like transcript receptor (ILT)‐4 secrete IL‐10 in response to Fc and adenosine

• Published in: European journal of immunology Vol. 48; no. 3; pp. 482 - 491
• Main Authors: Franco, Alessandra, Kumar, Jeetendra, Lin, Gene, Behnamfar, Negar, Hsieh, Li‐En, Shimizu, Chisato, Tremoulet, Adriana H., Burns, Jane C., Linden, Joel
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.03.2018
• Subjects: Adenosine; Adenosine - pharmacology; Antigen-presenting cells; CD11b; CD11b antigen; CD11c; CD11c antigen; CD14; CD14 antigen; CD4 antigen; CD4 Antigens - metabolism; Cell culture; Cell Differentiation; Child; Child, Preschool; Children; Cohort Studies; Constant region; Cyclic AMP; Cyclic AMP - metabolism; Cytokines; Dendritic cells; Dendritic Cells - classification; Dendritic Cells - drug effects; Dendritic Cells - immunology; Female; Humans; Immune Tolerance; Immunoglobulin Fc Fragments - administration & dosage; Immunoglobulins; Immunoregulation; Immunosuppression; In Vitro Techniques; Infant; Infants; Inflammation; Interleukin-10 - biosynthesis; Kawasaki disease; Lymphocytes; Lymphocytes T; Male; Membrane Glycoproteins - metabolism; Mucocutaneous Lymph Node Syndrome - immunology; Neoantigens; Pediatrics; Phenotypes; Receptor, Adenosine A2A - metabolism; Receptors, Immunologic - metabolism; Signal Transduction; Transcription; T cells; T cells; Kawasaki disease; CD14; CD11c; CD11b
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201747139

We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+CD11b+CD14+CD4+ and immunoglobulin‐like transcript receptor (ILT)‐4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)‐10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2AR), which, when activated by adenosine, inhibits the release of pro‐inflammatory cytokines from most immune cells. Here we show that stimulation of the A2AR on tmDCs by regadenoson or N‐ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL‐10 production under Fc stimulatory conditions. In co‐culture experiments, tmDCs inhibit the differentiation of naïve T cells to a pro‐inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children. Tolerogenic myeloid DCs express CD11c+CD11b+CD14+CD4+ILT‐4+ and downregulate inflammation by secretion of IL‐10 in response to Fc and A2AR stimulation.  ILT‐4 binds MHC class I acting as a negative KIR regulator. CD31 is very high in tmDCs suggesting a role for tmDCs in vascular homeostasis by binding CD38 on endothelial cells.