Novel Mouse Xenograft Models Reveal a Critical Role of CD4+ T Cells in the Proliferation of EBV-Infected T and NK Cells

PLoS Pathogens

Tomohiro Morio¹  Shigeyoshi Fujiwara¹  Osamu Miura²  Jun Komano³  Ayako Arai³  Ken-Ichi Imadome⁴  Fuyuko Kawano⁴  Misako Yajima⁴  Sayumi Ichikawa⁴  Mamoru Ito⁴  Atsuko Nakazawa⁵  Shouichi Ohga⁶  Hiroyuki Nakamura⁷  Naoki Yamamoto⁸  Norio Shimizu⁸ 

[1] AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan;Central Institute for Experimental Animals, Kawasaki, Japan;Department of Hematology, Tokyo Medical and Dental University, Tokyo, Japan;Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo, Japan;Department of Pathology, National Center for Child Health and Development, Tokyo, Japan;Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan;Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;Department of Virology, Division of Medical Science, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

关键词: Cytotoxic T cells;    NK cells;    T cells;    Liver transplantation;    Mouse models;    Blood;    Spleen;    Epstein-Barr virus;   

DOI  :  10.1371/journal.ppat.1002326

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic herpesvirus, ectopically infects T or NK cells to cause severe diseases of unknown pathogenesis, including chronic active EBV infection (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). We developed xenograft models of CAEBV and EBV-HLH by transplanting patients' PBMC to immunodeficient mice of the NOD/Shi-scid/IL-2Rγnull strain. In these models, EBV-infected T, NK, or B cells proliferated systemically and reproduced histological characteristics of the two diseases. Analysis of the TCR repertoire expression revealed that identical predominant EBV-infected T-cell clones proliferated in patients and corresponding mice transplanted with their PBMC. Expression of the EBV nuclear antigen 1 (EBNA1), the latent membrane protein 1 (LMP1), and LMP2, but not EBNA2, in the engrafted cells is consistent with the latency II program of EBV gene expression known in CAEBV. High levels of human cytokines, including IL-8, IFN-γ, and RANTES, were detected in the peripheral blood of the model mice, mirroring hypercytokinemia characteristic to both CAEBV and EBV-HLH. Transplantation of individual immunophenotypic subsets isolated from patients' PBMC as well as that of various combinations of these subsets revealed a critical role of CD4+ T cells in the engraftment of EBV-infected T and NK cells. In accordance with this finding, in vivo depletion of CD4+ T cells by the administration of the OKT4 antibody following transplantation of PBMC prevented the engraftment of EBV-infected T and NK cells. This is the first report of animal models of CAEBV and EBV-HLH that are expected to be useful tools in the development of novel therapeutic strategies for the treatment of the diseases.

【 授权许可】

CC BY