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.
Bibliographical noteFunding Information:
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.).