title: Aspirin-treated human DCs up-regulate ILT-3 and induce hyporesponsiveness and regulatory activity in responder T cells.
abstract: Mature dendritic cells (mDCs) are potent antigen presenting cells, but immature DCs (iDCs) have been shown to have reduced antigen stimulatory capacity. Different strategies have been investigated to augment the tolerogenic capacity of dendritic cells (DCs). We demonstrate that in aspirin-treated human DCs, there is reduced expression of CD1a, HLA-DR and CD86, up-regulation of ILT-3 expression and marginal increases in PDL-1. Aspirin-treated DCs are partially resistant to phenotypic changes following maturational stimuli, such as lipopolysaccharide (LPS) or TNFalpha, IL-1alpha and PGE2. Aspirin-treated DCs demonstrate normal endocytic function, but have a reduced ability to stimulate allogeneic T cells, which is comparable to iDCs. Furthermore, they induce hyporesponsiveness and regulatory activity in responder naïve and memory T cells; for naïve T cells this is achieved more quickly and efficiently than with iDCs. We investigated the mechanism of this regulatory activity and found that both cell-cell contact and inhibitory cytokine activity are involved, although no one cytokine predominates in importance. Blocking ILT-3 or IL-12 does not diminish the capacity of these DCs to induce regulation or Foxp3 expression on the regulatory T cells. Results demonstrate that aspirin-treated DCs display tolerogenic potential, which is of interest in their therapeutic potential in reducing chronic allograft rejection.
authors.affiliation: Immunoregulation Laboratories, Department of Nephrology and Transplantation, King's College London School of Medicine at Guy's, King's College and St. Thomas' Hospitals, London, SE1 9RT, UK.
authors.forename: M
authors.initials: M
authors.lastname: Buckland
authors.forename: C B
authors.initials: CB
authors.lastname: Jago
authors.forename: H
authors.initials: H
authors.lastname: Fazekasova
authors.forename: K
authors.initials: K
authors.lastname: Scott
authors.forename: P H
authors.initials: PH
authors.lastname: Tan
authors.forename: A J T
authors.initials: AJ
authors.lastname: George
authors.forename: R
authors.initials: R
authors.lastname: Lechler
authors.forename: G
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017951:Antigen Presentation; D001241:Aspirin / Q000494:pharmacology*; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D011971:Receptors, Immunologic; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C107907:LILRB4 protein, human; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D018664:Interleukin-12; D001241:Aspirin