Article

Functional Impairment of CD8+ T Cells by Regulatory T Cells during Persistent Retroviral Infection

Institut für Virologie des Universitätsklinikums, 45122 Essen, Germany.
Immunity (Impact Factor: 19.75). 04/2004; 20(3):293-303. DOI: 10.1016/S1074-7613(04)00054-8
Source: PubMed

ABSTRACT The establishment of viral persistence generally requires evasion of the host CD8(+) T cell response. Here we describe a form of evasion wherein the CD8(+) T cells are fully capable of recognizing their cognate antigen but their effector functions are suppressed by regulatory T cells. Virus-specific CD8(+) T cells adoptively transferred into mice persistently infected with Friend virus proliferated and appeared activated, but failed to produce IFNgamma or reduce virus loads. Cotransfer experiments revealed that a subpopulation of CD4(+) T cells from persistently infected mice suppressed IFNgamma production by the CD8(+) T cells. Treatment of persistently infected mice with anti-GITR antibody to ameliorate suppression by regulatory T cells significantly improved IFNgamma production by transferred CD8(+) T cells and allowed a significant reduction in viral loads. The results indicate that CD4(+) regulatory T cells contribute to viral persistence and demonstrate an immunotherapy for treating chronic retroviral infections.

Download full-text

Full-text

Available from: Leonard H Evans, Jul 02, 2015
0 Followers
 · 
145 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10-100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.
    Journal of Experimental Medicine 08/2014; 211(9). DOI:10.1084/jem.20132577 · 13.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The influence of CD25(+)CD4(+) regulatory T cells (Treg) on acute and chronic viral infection of the central nervous system (CNS) was examined using a glial tropic murine coronavirus. Treg in the CNS were highest during initial T cell mediated virus control, decreased and then remained relatively stable during persistence. Anti-CD25 treatment did not affect CNS recruitment of inflammatory cells. Viral control was initially delayed; however, neither the kinetics of viral control nor viral persistence were affected. By contrast, the absence of Treg during the acute phase resulted in increased demyelination during viral persistence. These data suggest that CNS inflammation, progression of viral control and viral persistence are relatively independent of CD25(+)CD4(+) Treg. However, their absence during acute infection alters the ability of the host to limit tissue damage.
    Virology 12/2013; 447(1-2):112-20. DOI:10.1016/j.virol.2013.08.030 · 3.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: As many members of the tumor necrosis factor receptor superfamily, glucocorticoid-induced TNFR-related gene (GITR) plays multiple roles mostly in the cells of immune system. CD8(+) T cells are key players in the immunity against viruses and tumors, and GITR has been demonstrated to be an essential molecule for these cells to mount an immune response. The aim of this paper is to focus on GITR function in CD8(+) cells, paying particular attention to numerous and recent studies that suggest its crucial role in mouse disease models.
    The Scientific World Journal 04/2012; 2012:308265. DOI:10.1100/2012/308265 · 1.73 Impact Factor