Role of regulatory T cells in coronavirus-induced acute encephalitis

Abstract

C57BL/6 mice 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.MY135Q) results in a nonlethal disease. Increased mortality correlated with a greater number of JHMV-specific CD4 T cells in the brains of rJ compared to rJ.MY135Q-infected mice. Here, we extend these results to show that the diminished number of virus-specific T cells correlates with a reduced cytokine/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 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-specific effector T cells and anti-inflammatory elements, such as Tregs. These findings 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.

Role of CD4+ T Cells in the Pathophysiology of Multiple Sclerosis

“…In contrast, when SJL/J mice were treated with iTregs during the late phase of TMEV infection (iTreg-late), iTreg-late SJL/J mice developed less CNS inflammatory demyelination and a greater amount of IL-10 production, compared with untreated control mice. Here, IL-10 was produced from multiple cell types, including CD4 + and CD8 + T cells, B cells, macrophages, and DCs, which was consistent with the findings that Tregs could induce IL-10 production from other cell types (Anghelina, Zhao, Trandem, & Perlman, 2009;Kearley, Barker, Robinson, & Lloyd, 2005). The contrasting effects of iTregs in TMEV infection suggested that Tregs could be beneficial by suppressing immunopathology, when CNS viral loads were low (iTreg-late) as seen with persistent viral infection, while Tregs could be detrimental by suppressing antiviral immunity, when viral replication is active (iTreg-early) as in acute viral infection.…”

Chemokine CXCL10 and Coronavirus-Induced Neurologic Disease

“…Further, virus-specific Tregs express both IFN-c and IL-10 suggesting immune regulatory capacities mediated through cytokines secreted following antigen stimulation. Indeed, virus-specific Tregs dampen proliferation of virus-specific effector CD4 + T cells, and depletion of Tregs increases mortality (2,102). These data suggest that within the context of acute JHMV-induced neurologic disease, Tregs limit immunopathological CNS disease without negatively impacting viral clearance (2).…”

“…i.c., intracranial; NK, natural killer. More recently, Perlman and colleagues have provided important insight into the functional role of regulatory T cells (Tregs) during acute JHMV-induced CNS disease (2,102). Tregs are detected within the CNS at the same time as effector CD4 + T cells, indicating that the emergence and accumulation of both populations of cells are on a similar timeline following viral infection.…”

Intranasal administration of IL-35 inhibits allergic responses and symptoms in mice with allergic rhinitis

“…33 Induced Tregs in coronaviral infection also protects against greater severity of the disease. 34 Anghelina et al 35 showed that Tregs depletion resulted in increased mortality in coronavirus-induced acute encephalitis, and transfer of Tregs increased survival from 0% to 50%. At the moment, the association between Tregs and airway infection is unclear.…”

“…8e10 Huang et al 8 showed that IL-4, IL-5, and IL-13 in BALF were inhibited by administration of plasmid DNA encoding recombinant single-chain IL-35. Dong et al 9 also reported that administration of recombinant fusion protein of murine IL- 35 and human Fc fragment (rIL-35) reduced eosinophil counts in BALF. Li et al 10 documented a reduction in the numbers of inflammatory cells and levels of IL-4, IL-5, IL-13, and IL-17 in BALF with administration of adenovirus expressing IL-35.…”