title: Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice.
abstract: Whereas humanized mouse models have contributed significantly to human immunology research, human T cells developing in mouse thymic environment fail to demonstrate HLA-restricted function. To achieve HLA-restricted human immune response, we created an immune-compromised non-obese diabetic/SCID/IL2rg(null) strain (NSG) with homozygous expression of HLA class I heavy chain and light chain (NSG-HLA-A2/HHD). Transplantation of purified Lin-CD34+CD38- human hematopoietic stem cells into NSG-HLA-A2/HHD newborns resulted in the development of human CD4+ and CD8+ TCR alphabeta+ T cells and CD4-CD8- and CD8+ TCR gammadelta+ cells in recipient bone marrow and spleen. Human cytotoxic T lymphocytes (CTLs) become functionally mature, as evidenced by the production of granzyme corresponding to phenotypic transition from naïve to effector memory CTLs. In these recipients, human Th17 cells developed along with Th1 and Th2 cells. Epstein-Barr virus (EBV) infection in the humanized NSG-HLA-A2/HHD recipients resulted in the formation of lymphoproliferative lesions consisting mainly of human B cells with scattered human T cells. Human CTLs developing in the recipients recognized EBV-derived peptides in an HLA-restricted manner and exerted HLA-restricted cytotoxicity against EBV-infected human B cells. The HLA-expressing humanized mouse with functional HLA-restricted T cells and consistent representation of rare T-cell subsets overcomes a major constraint in human immunology, and serves as a useful model for investigation of human immune responses against pathogens and for the development of therapeutic strategies against human diseases.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609.
authors.forename: Leonard D
authors.initials: LD
authors.lastname: Shultz
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Saito
authors.forename: Yuho
authors.initials: Y
authors.lastname: Najima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tanaka
authors.forename: Toshiki
authors.initials: T
authors.lastname: Ochi
authors.forename: Mariko
authors.initials: M
authors.lastname: Tomizawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Doi
authors.forename: Akiko
authors.initials: A
authors.lastname: Sone
authors.forename: Nahoko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic; D020031:Epstein-Barr Virus Infections / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency* / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013045:Species Specificity; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000821:virology
chemical_list: D015789:HLA-A2 Antigen; D053631:Interleukin Receptor Common gamma Subunit