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1、Role of regulatory T cells in coronavirus-induced acute encephalitis Daniela Anghelina a, Jingxian Zhaoa, Kathryn Trandemb, Stanley Perlmana,b, a Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA b Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 5224
2、2, USA a b s t r a c ta r t i c l ei n f o Article history: Received 18 September 2008 Returned to author for revision 29 October 2008 Accepted 9 December 2008 Available online 11 January 2009 Keywords: Rodent model Coronavirus Regulatory T cells Effector CD4 T cells Acute encephalitis C57BL/6 mice
3、infected with mouse hepatitis virus, strain JHM (JHMV) develop a rapidly fatal acute encephalitis. Previously, we showed that this disease is partially CD4 T cell-mediated since infection with a recombinant JHMV (rJ) mutated in only a single immunodominant CD4 T cell epitope (epitope M133, rJ. MY135
4、Q ) results in a nonlethal disease. Increased mortality correlated with a greater number of JHMV-specifi c CD4 Tcells in the brains of rJ compared to rJ.MY135Q-infected mice. Here, we extend these results to show that the diminished number of virus-specifi c T cells correlates with a reduced cytokin
5、e/chemokine response in the infected brain. We also show that regulatory CD4 T cells (Tregs) are critical for mild disease in rJ.MY135Q- infected mice because their depletion results in increased mortality. Further, a relative paucity of Tregs characterizes lethal infection because adoptive transfer
6、 of Tregs into rJ-infected mice increases survival from 0% to 50%. These results support the notion that clinical disease in coronavirus-induced acute encephalitis results from a balance between factors critical for virus clearance, such as virus-specifi c effector T cells and anti-infl ammatory ele
7、ments, such as Tregs. These fi ndings also show that unlike chronic infections, in which an excessive number of Tregs contributes to pathogen persistence, Tregs in the setting of acute encephalitis may help to limit immunopathological disease without delaying virus clearance. 2008 Elsevier Inc. All
8、rights reserved. Introduction The outcome of viral infections is dependent upon complex interactions between the pathogen and host pro- and anti- infl ammatory immune responses. A dysregulated and overexuberant innate immune response has been implicated in fatal H5N1 infl uenza (de Jong et al., 2006
9、) and may also be involved in the pathogenesis of SARS (Severe Acute Respiratory Syndrome), caused by a novel coronavirus (Perlman and Dandekar, 2005). Excessive T cell responses have also been implicated in disease in mice infected with lymphocytic choriomeningitis virus (LCMV), herpes simplex viru
10、s or respiratory syncytial virus, with tissue damage occurring during the process of virus clearance (Hussell et al., 2001; Oldstone, 2002; Suvas et al., 2004). To minimize excessive pro-infl ammatory responses, cells with anti-infl ammatory activity, such as regulatory T cells and Tr1 cells, which
11、express IL-10 (Roncarolo et al., 2006), are also induced during a normal immune response. An appropriate anti-infl ammatory response will prevent immunopathological dis- ease without adversely affecting virus clearance. Regulatory T cells, which suppress the pro-infl ammatory response, encompass sev
12、eral subsets including thymically derived CD4+CD25+cells that express the transcription factor Foxp3 (natural Tregs, abbreviated Tregs herein) (Belkaid, 2007; Roncarolo and Battaglia, 2007). Many studies have assessed the role of Tregs in autoimmunity, where a relative defi ciency of these cells occ
13、urs, and cancer, where they inhibit anti- tumor T cell responses (Nomura and Sakaguchi, 2005; Sakaguchi, 2005; Sakaguchi et al., 2006). These cells have also been implicated in chronic viral diseases. This was fi rst demonstrated in mice infected with Friends virus or herpes simplex virus and subse-
14、 quently in humans infected with viruses such as hepatitis C virus (HCV) and HIV (Belkaid, 2007; Belkaid and Rouse, 2005; Iwashiro et al., 2001; MacDonald et al., 2002; Robertson and Hasenkrug, 2006; Suvas et al., 2004). In infectious settings, Tregs can dampen the immune response, thus minimizing t
15、issue damage but at the cost of inhibiting virus clearance (reviewed in Belkaid, 2007; Belkaid and Rouse, 2005; Robertson and Hasenkrug, 2006). Tregs might be predicted to have a lesser role in acute viral diseases, since these infections are often characterized by uncon- trolled virus replication a
16、nd rapid disease progression. In murine coronavirus-induced acute encephalitis, mice infected with the neurovirulent JHM strain (JHMV) of mouse hepatitis virus (MHV) develop a fatal disease with death occurring at 78 days p.i. (Stohlman et al., 1998). Virus-specifi c T cells are fi rst detected in the brain at 6 days p.i., 2448 h prior to the death of the animals. In C57BL/6 (B6) mice, the majority of brain-derived CD8 Tcells recognize two epitopes in the surface (S) glycoprotein (S510 and S598
