FLT3-ligand treatment of humanized mice results in the generation of large numbers of CD141+ and CD1c+ dendritic cells in vivo

J Immunol. 2014 Feb 15;192(4):1982-9. doi: 10.4049/jimmunol.1302391. Epub 2014 Jan 22.

Abstract

We established a humanized mouse model incorporating FLT3-ligand (FLT3-L) administration after hematopoietic cell reconstitution to investigate expansion, phenotype, and function of human dendritic cells (DC). FLT3-L increased numbers of human CD141(+) DC, CD1c(+) DC, and, to a lesser extent, plasmacytoid DC (pDC) in the blood, spleen, and bone marrow of humanized mice. CD1c(+) DC and CD141(+) DC subsets were expanded to a similar degree in blood and spleen, with a bias toward expansion of the CD1c(+) DC subset in the bone marrow. Importantly, the human DC subsets generated after FLT3-L treatment of humanized mice are phenotypically and functionally similar to their human blood counterparts. CD141(+) DC in humanized mice express C-type lectin-like receptor 9A, XCR1, CADM1, and TLR3 but lack TLR4 and TLR9. They are major producers of IFN-λ in response to polyinosinic-polycytidylic acid but are similar to CD1c(+) DC in their capacity to produce IL-12p70. Although all DC subsets in humanized mice are efficient at presenting peptide to CD8(+) T cells, CD141(+) DC are superior in their capacity to cross-present protein Ag to CD8(+) T cells following activation with polyinosinic-polycytidylic acid. CD141(+) DC can be targeted in vivo following injection of Abs against human DEC-205 or C-type lectin-like receptor 9A. This model provides a feasible and practical approach to dissect the function of human CD141(+) and CD1c(+) DC and evaluate adjuvants and DC-targeting strategies in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / administration & dosage
  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antigen Presentation / immunology
  • Antigens, CD / immunology
  • Antigens, CD1 / metabolism*
  • Antigens, Surface / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules / metabolism
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology*
  • Female
  • Glycoproteins / metabolism*
  • Humans
  • Immunoglobulins / metabolism
  • Interferon-gamma / metabolism
  • Interleukin-12 / metabolism
  • Lectins, C-Type / immunology
  • Lectins, C-Type / metabolism
  • Lymphocyte Activation / immunology
  • Membrane Proteins / administration & dosage
  • Membrane Proteins / pharmacology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Minor Histocompatibility Antigens
  • Poly I-C / immunology
  • Receptors, Cell Surface / immunology
  • Receptors, Chemokine / metabolism
  • Thrombomodulin
  • Toll-Like Receptor 3 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Toll-Like Receptor 9 / metabolism

Substances

  • Adjuvants, Immunologic
  • Antigens, CD
  • Antigens, CD1
  • Antigens, Surface
  • CD1C protein, human
  • Cadm1 protein, mouse
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • DEC-205 receptor
  • Glycoproteins
  • Immunoglobulins
  • Lectins, C-Type
  • Membrane Proteins
  • Minor Histocompatibility Antigens
  • Receptors, Cell Surface
  • Receptors, Chemokine
  • THBD protein, human
  • TLR3 protein, mouse
  • Thrombomodulin
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • XC chemokine receptor 1, mouse
  • flt3 ligand protein
  • Interleukin-12
  • Interferon-gamma
  • Poly I-C