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Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1

Nature Medicine volume 12, pages 1316–1322 (2006)Cite this article

Abstract

Here we show that transplantation of autologous human hematopoietic fetal liver CD34+ cells into NOD/SCID mice previously implanted with human fetal thymic and liver tissues results in long-term, systemic human T-cell homeostasis. In addition, these mice show systemic repopulation with human B cells, monocytes and macrophages, and dendritic cells (DCs). T cells in these mice generate human major histocompatibility complex class I– and class II–restricted adaptive immune responses to Epstein-Barr virus (EBV) infection and are activated by human DCs to mount a potent T-cell immune response to superantigens. Administration of the superantigen toxic shock syndrome toxin 1 (TSST-1) results in the specific systemic expansion of human Vβ2+ T cells, release of human proinflammatory cytokines and localized, specific activation and maturation of human CD11c+ dendritic cells. This represents the first demonstration of long-term systemic human T-cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1.

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Figure 1: Human reconstitution of NOD/SCID-hu thy-liv mice transplanted with autologous human hematopoietic stem cells.
Figure 2: Human hematopoietic cells in BLT mice.
Figure 3: Human thymopoiesis and Vβ T-cell diversity in BLT mice.
Figure 4: Analysis of the human T-cell adaptive immune response to EBV infection in BLT mice.
Figure 5: Innate immune response to TSST-1.

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Acknowledgements

The authors thank M. Islas-Ohlmayer, P. Cravens, M.P. Martin, Z. Sun, A. Curry, S. O'Reilly and R. Getachew for their participation in this study, for the cytokine assay and for assistance with animal care. We thank J. Sixbey for the stock of Akata virus, A. Leen and C. Rooney for their assistance with the establishment of the LCLs and the ELISPOT analysis, K. Hamra and D. Garbers for use of their dissecting microscope and assistance collecting the ELISPOT images, M. Bennett, D. Douek, L. Picker, L. Schultz and J. McCune for their support and contribution to the early stages of this project, J. Tew and M. Kosco-Vilbois for advice and expert discussion regarding the organization of secondary lymphoid tissues, and D. Autry for graphic art assistance. Cord blood samples were provided by the Department of Obstetrics and Gynecology's Tissue Procurement Facility of the University of Texas Southwestern Medical Center at Dallas (US National Institutes of Health (NIH) grant HD011149). This work was supported in part by NIH grants R37 AI028246 (A.T.H.), CA82055 and AI39416 (J.V.G.) and training grants 5T32 AI005284 (P.W.D.) and T32 AI07421 (J.D.E.).

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, Dallas, 75390, Texas, USA

    Michael W Melkus, Angela Padgett-Thomas, Paul W Denton, Florence A Othieno, Anja K Wege & J Victor Garcia

  2. Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, 55455, Minnesota, USA

    Jacob D Estes & Ashley T Haase

  3. Arena Pharmaceuticals Inc., 6161 Nancy Ridge Drive, San Diego, 92121, California, USA

    Joel Gatlin

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Correspondence to J Victor Garcia.

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Supplementary information

Supplementary Fig. 1

Immunohistological staining for human CD45+ cells and lineage-specific hematopoietic markers in BLT liver compared to human liver. (PDF 145 kb)

Supplementary Fig. 2

Analysis of EGFP expression in different hematopoietic cell subsets after transplantation with CD34+ cells transduced with a lentivirus-based vector. (PDF 100 kb)

Supplementary Fig. 3

Immunohistological analysis of secondary lymhoid tissues of BLT mice. (PDF 214 kb)

Supplementary Fig. 4

Spleen CD123+ human DCs do not respond to TSST-1. (PDF 65 kb)

Supplementary Table 1

Analysis of human CD4+ and CD8+ T cells in different tissues from BLT mice. (PDF 38 kb)

Supplementary Table 2

Naive versus memory phenotype of human peripheral blood T cells in BLT mice. (PDF 31 kb)

Supplementary Methods (PDF 95 kb)

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Melkus, M., Estes, J., Padgett-Thomas, A. et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med 12, 1316–1322 (2006). https://doi.org/10.1038/nm1431

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