HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis.

Ito, Kouichi; Bian, Hongjin; Molina, Margarita; Han, Jaeseok; Magram, Jeanne; Saar, Efrat Glick; Belunis, Charles; Bolin, David; Arceo, R; Campbell, Robert M.; Falcioni, Fiorenza; Vidovic, Damir; Hammer, Jürgen; Nagy, Zoltán Á.

doi:10.1084/jem.183.6.2635

Cited by 176 publications

(155 citation statements)

References 34 publications

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“…Some V␤-bearing subfamilies (such as V␤8 family) appeared overrepresented in CD4 T cells from YAC ϩ mice (Fig. 4C), perhaps reflecting deletion of V␤5-, V␤11-, and V␤12-bearing T cells due to endogenous expression of mouse mammary tumor virus superantigens (47). A similar deletion pattern occurred in the CD8 T cell compartment of YAC ϩ mice, although V␤5-bearing CD8 T cells were barely detectable even in normal B6 mice.…”

Section: Positive and Negative Selection Of Cd4 T Cells In Yac-transgmentioning

confidence: 51%

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

Chen

Dudek

Wijburg

et al. 2002

The Journal of Immunology

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MHC class II haplotypes control the specificity of Th immune responses and susceptibility to many autoimmune diseases. Understanding the role of HLA class II haplotypes in immunity is hampered by the lack of animal models expressing these genes as authentic cis-haplotypes. In this study we describe transgenic expression of the autoimmune prone HLA DR3-DQ2 haplotype from a yeast artificial chromosome (YAC) containing an intact ∼320-kb region from HLA DRA to DQB2. In YAC-transgenic mice HLA DR and DQ gene products were expressed on B cells, macrophages, and dendritic cells, but not on T cells indicating cell-specific regulation. Positive selection of the CD4 compartment by human class II molecules was 67% efficient in YAC-homozygous mice lacking endogenous class II molecules (Aβnull/null) and expressing only murine CD4. A broad range of TCR Vβ families was used in the peripheral T cell repertoire, which was also purged of Vβ5-, Vβ11-, and Vβ12-bearing T cells by endogenous mouse mammary tumor virus-encoded superantigens. Expression of the HLA DR3-DQ2 haplotype on the Aβnull/null background was associated with normal CD8-dependent clearance of virus from influenza-infected mice and development of CD4-dependent protection from otherwise lethal infection with Salmonella typhimurium. HLA DR- and DQ-restricted T cell responses were also elicited following immunization with known T cell determinants presented by these molecules. These findings demonstrate the potential for human MHC class II haplotypes to function efficiently in transgenic mice and should provide valuable tools for developing humanized models of MHC-associated autoimmune diseases.

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Section: Positive and Negative Selection Of Cd4 T Cells In Yac-transgmentioning

confidence: 51%

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

Chen

Dudek

Wijburg

et al. 2002

The Journal of Immunology

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“…DR4 tg mice on a B6 background are devoid of endogenous MHC class II but express a chimeric HLA molecule composed of HLA-DRA-IEa and HLA-DRB1*0401-IEb. 60 Ja18 À/À mice, also on B6 background, which selectively lack iNKT cells, 61 were obtained from Dr Luc Van Kaer (Vanderbilt University, Nashville, TN, USA). DR4 tg mice and Ja18 À/À mice were bred in a barrier facility at the University of Western Ontario (london, Ontario, Canada).…”

Section: Methods Micementioning

confidence: 99%

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

et al. 2011

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Invariant NKT (iNKT) cells are infrequent but important immunomodulatory lymphocytes that exhibit CD1d-restricted reactivity with glycolipid Ags. iNKT cells express a unique T-cell receptor (TCR) composed of an invariant a-chain, paired with a limited range of b-chains. Superantigens (SAgs) are microbial toxins defined by their ability to activate conventional T cells in a TCR b-chain variable domain (Vb)-specific manner. However, whether iNKT cells are directly activated by bacterial SAgs remains an open question. Herein, we explored the responsiveness of mouse and human iNKT cells to a panel of staphylococcal and streptococcal SAgs and examined the contribution of major histocompatibility complex (MHC) class II and CD1d to these responses. Bacterial SAgs that target mouse Vb8, such as staphylococcal enterotoxin B (SEB), were able to activate mouse hybridoma and primary hepatic iNKT cells in the presence of mouse APCs expressing human leukocyte antigen (HLA)-DR4. iNKT cell-mediated cytokine secretion in SEB-challenged HLA-DR4-transgenic mice was CD1d-independent and accompanied by a high interferon-c:interleukin-4 ratio consistent with an in vivo Th1 bias. Furthermore, iNKT cells from SEB-injected HLA-DR4-transgenic mice, and iNKT cells from SEB-treated human PBMCs, showed early activation by intracellular cytokine staining and CD69 expression. Unlike iNKT cell stimulation by a-galactosylceramide, stimulation by SEB did not induce TCR downregulation of either mouse or human iNKT cells. We conclude that Vb8-targeting bacterial SAgs can activate iNKT cells by utilizing a novel pathway that requires MHC class II interactions, but not CD1d. Therefore, iNKT cells fulfill important effector functions in response to bacterial SAgs and may provide attractive targets in the management of SAg-induced illnesses.

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“…Murine class II-deficient, DR4-IE Tg mice express HLA-DRA-IE-␣ and HLA-DRB1*0401-IE-␤ chimeric genes containing the Ag-binding ␣1 and ␤1 domains from the human HLA-DRA and HLA-DRB1*0401 molecules, respectively, with the remaining domains comprised of murine IE d -␣2 and IE d -␤2 chains (32). Female DR4-IE Tg mice 6-to 10-wk-old were used for all experiments.…”

Section: Animalsmentioning

confidence: 99%

“…Founder mice were obtained through Paul Lehmann (at Case Western Reserve University, Cleveland, OH) and maintained and bred in a barrier facility (Biocon, Rockville, MD). Mice were confirmed to have two allelic copies of the DR4-IE chimeric transgene using PCR amplification of genomic DNA (oligonucleotide primers previously described (32)). Eighty microsatellite markers (Research Genetics, Huntsville, AL), evenly distributed across the murine genome, were used to assess genetic similarity to C57BL/6n mice (33).…”

Section: Animalsmentioning

confidence: 99%

Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice

Touloukian

Leitner

Topalian

et al. 2000

The Journal of Immunology

115

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CD4+ T cells play a central role in the induction and persistence of CD8+ T cells in several models of autoimmune and infectious disease. To improve the efficacy of a synthetic peptide vaccine based on the self-Ag, gp100, we sought to provide Ag-specific T cell help. To identify a gp100 epitope restricted by the MHC class II allele with the highest prevalence in patients with malignant melanoma (HLA-DRB1*0401), we immunized mice transgenic for a chimeric human-mouse class II molecule (DR4-IE) with recombinant human gp100 protein. We then searched for the induction of CD4+ T cell reactivity using candidate epitopes predicted to bind to DRB1*0401 by a computer-assisted algorithm. Of the 21 peptides forecasted to bind most avidly, murine CD4+ T cells recognized the epitope (human gp10044–59, WNRQLYPEWTEAQRLD) that was predicted to bind best. Interestingly, the mouse helper T cells also recognized human melanoma cells expressing DRB1*0401. To evaluate whether human CD4+ T cells could be generated from the peripheral blood of patients with melanoma, we used the synthetic peptide h-gp10044–59 to sensitize lymphocytes ex vivo. Resultant human CD4+ T cells specifically recognized melanoma, as measured by tumor cytolysis and the specific release of cytokines and chemokines. HLA class II transgenic mice may be useful in the identification of helper epitopes derived from Ags of potentially great clinical utility.

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HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis.

Cited by 176 publications

References 34 publications

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

Identification of a MHC Class II-Restricted Human gp100 Epitope Using DR4-IE Transgenic Mice

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