Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells.
In mouse, a subset of dendritic cells (DCs) known as CD8alpha+ DCs has emerged as an important player in the regulation of T cell responses and a promising target in vaccination strategies. However, translation into clinical protocols has been hampered by the failure to identify CD8alpha+ DCs in humans. Here, we characterize a population of human DCs that expresses DNGR-1 (CLEC9A) and high levels of BDCA3 and resembles mouse CD8alpha+ DCs in phenotype and function. We describe the presence of such cells in the spleens of humans and humanized mice and report on a protocol to generate them in vitro. Like mouse CD8alpha+ DCs, human DNGR-1+ BDCA3hi DCs express Necl2, CD207, BATF3, IRF8, and TLR3, but not CD11b, IRF4, TLR7, or (unlike CD8alpha+ DCs) TLR9. DNGR-1+ BDCA3hi DCs respond to poly I:C and agonists of TLR8, but not of TLR7, and produce interleukin (IL)-12 when given innate and T cell-derived signals. Notably, DNGR-1+ BDCA3+ DCs from in vitro cultures efficiently internalize material from dead cells and can cross-present exogenous antigens to CD8+ T cells upon treatment with poly I:C. The characterization of human DNGR-1+ BDCA3hi DCs and the ability to grow them in vitro opens the door for exploiting this subset in immunotherapy.
Poulin
Lionel Franz
LF
Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, UK.
Salio
Mariolina
M
Griessinger
Emmanuel
E
Anjos-Afonso
Fernando
F
Craciun
Ligia
L
Chen
Ji-Li
JL
Keller
Anna M
AM
Joffre
Olivier
O
Zelenay
Santiago
S
Nye
Emma
E
Le Moine
Alain
A
Faure
Florence
F
Donckier
Vincent
V
Sancho
David
D
Cerundolo
Vincenzo
V
Bonnet
Dominique
D
Reis e Sousa
Caetano
C
D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D045142:Cross-Priming / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D004705:Endocytosis / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D018664:Interleukin-12 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D011070:Poly I-C / Q000494:pharmacology; D011975:Receptors, Mitogen / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018180:Thrombomodulin; D051193:Toll-Like Receptors / Q000819:agonists
D000954:Antigens, Surface; C530206:CLEC9a protein, human; D037181:Lectins, C-Type; D011975:Receptors, Mitogen; C546931:THBD protein, human; D018180:Thrombomodulin; D051193:Toll-Like Receptors; D018664:Interleukin-12; D011070:Poly I-C