Human NK cells of mice with reconstituted human immune system components require preactivation to acquire functional competence.
To investigate human natural killer (NK)-cell reactivity in vivo we have reconstituted human immune system components by transplantation of human hematopoietic progenitor cells into NOD-scid IL2Rγ(null) mice. We demonstrate here that this model allows the development of all NK-cell subsets that are also found in human adult peripheral and cord blood, including NKp46(+)CD56(-) NK cells. Similar to human cord blood, NK cells from these reconstituted mice require preactivation by interleukin-15 to reach the functional competence of human adult NK cells. Mainly the terminally differentiated CD16(+) NK cells demonstrate lower reactivity without this stimulation. After preactivation, both CD16(+) and CD16(-) NK cells efficiently produce interferon-γ and degranulate in response to stimulation with NK cell-susceptible targets, including K562 erythroleukemia cells. NK-cell lines, established from reconstituted mice, demonstrate cytotoxicity against this tumor cell line. Importantly, preactivation can as well be achieved by bystander cell maturation via poly I:C stimulation in vitro and injection of this maturation stimulus in vivo. Preactivation in vivo enhances killing of human leukocyte antigen class I negative tumor cells after their adoptive transfer. These data suggest that a functional, but resting, NK-cell compartment can be established in immune-compromised mice after human hematopoietic progenitor cell transfer.
Strowig
Till
T
Laboratory of Viral Immunobiology, and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA.
Chijioke
Obinna
O
Carrega
Paolo
P
Arrey
Frida
F
Meixlsperger
Sonja
S
Rämer
Patrick C
PC
Ferlazzo
Guido
G
Münz
Christian
C
D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D053804:Granzymes / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000276:immunology*; D007121:Immunocompetence / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D054353:Perforin / Q000378:metabolism; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000378:metabolism
D018952:Antigens, CD34; D019002:CD56 Antigen; D019409:Interleukin-15; D055627:Natural Cytotoxicity Triggering Receptor 1; D015375:Receptors, Interleukin-2; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes; D011070:Poly I-C