The analysis of the functions of human B and T cells in humanized NOD/shi-scid/gammac(null) (NOG) mice (hu-HSC NOG mice).
'Humanized mice' are anticipated to be a valuable tool for studying the human immune system, but the reconstituted human immune cells have not yet been well characterized. Here, we extensively investigated the differentiation and functions of human B and T cells in a supra-immunodeficient mouse strain, NOD/shi-scid/gammac(null) (NOG) reconstituted with CD34(+) hematopoietic stem cells obtained from umbilical cord blood. In these hu-HSC NOG mice, the development of human B cells was partially blocked, and a significant number of B-cell progenitors accumulated in the spleen. The mature CD19(+)IgM(+)IgD(+) human B cells of the hu-HSC NOG mice could produce IgG in vivo and in vitro by antigenic stimulation. In contrast, although human T cells with an apparently normal phenotype developed, most of them could neither proliferate nor produce IL-2 in response to antigenic stimulation by anti-CD3 and anti-CD28 antibodies in vitro. The positive selection of human T cells in the thymus was sufficiently functional, if not complete, and mainly mediated by mouse class II, suggesting that the human T cells lost their function in the periphery. We found that multiple mechanisms were involved in the T-cell abnormalities. Collectively, our results demonstrate that further improvements are necessary before humanized mice with a functional human immune system are achieved.
Watanabe
Yohei
Y
Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
Takahashi
Takeshi
T
Okajima
Akira
A
Shiokawa
Miho
M
Ishii
Naoto
N
Katano
Ikumi
I
Ito
Ryoji
R
Ito
Mamoru
M
Minegishi
Masayoshi
M
Minegishi
Naoko
N
Tsuchiya
Shigeru
S
Sugamura
Kazuo
K
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000276:immunology; D018952:Antigens, CD34 / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D005312:Fetal Blood / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D000098546:Interleukin-21; D000099176:Noggin Protein
D000906:Antibodies; D018952:Antigens, CD34; D018106:CD28 Antigens; D017252:CD3 Complex; D019013:CD40 Antigens; D002352:Carrier Proteins; D007074:Immunoglobulin G; D007376:Interleukin-2; D007378:Interleukins; D000098546:Interleukin-21; D000099176:Noggin Protein