FLT3-ligand treatment of humanized mice results in the generation of large numbers of CD141+ and CD1c+ dendritic cells in vivo.
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.
Mater Research, Translational Research Institute, Brisbane, Queensland 4102, Australia;
Yitian
Y
Ding
Andrew
A
Wilkinson
Adi
A
Idris
Ben
B
Fancke
Meredith
M
O'Keeffe
Dalia
D
Khalil
Xinsheng
X
Ju
Mireille H
MH
Lahoud
Irina
I
Caminschi
Ken
K
Shortman
Robyn
R
Rodwell
Slavica
S
Vuckovic
Kristen J
KJ
Radford
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D018949:Antigens, CD1 / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015778:Minor Histocompatibility Antigens; D011070:Poly I-C / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D019707:Receptors, Chemokine / Q000378:metabolism; D018180:Thrombomodulin; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D018949:Antigens, CD1; D000954:Antigens, Surface; C437944:CD1C protein, human; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; C093569:DEC-205 receptor; D006023:Glycoproteins; D007136:Immunoglobulins; D037181:Lectins, C-Type; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; C546931:THBD protein, human; C519703:TLR3 protein, mouse; D018180:Thrombomodulin; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C551408:XC chemokine receptor 1, mouse; C084881:flt3 ligand protein; D018664:Interleukin-12; D007371:Interferon-gamma; D011070:Poly I-C