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: 21.56). 04/2004; 20(3):293-303. DOI: 10.1016/S1074-7613(04)00054-8
Source: PubMed


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


Available from: Leonard H Evans
  • Source
    • "Thus, conventional CD4 T cells have a positive impact on modulating CD8 T cell function during persistent antigenic stimulation . In contrast, it has been described that T reg cells are detrimental to virus-specific T cell responses during persistent infection in mice (Dittmer et al., 2004; Dietze et al., 2011; Schmitz et al., 2013); nevertheless, the role of T reg cells in maintaining T cell exhaustion has not been well characterized or fully explored as a therapeutic approach. "
    [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.
    Full-text · Article · Aug 2014 · Journal of Experimental Medicine
  • Source
    • "Exuberant T cell effector function and tissue damage are regulated by sustained natural Treg (nTreg), induction of antigen specific Foxp3 þ Treg (iTreg), secretion of the antiinflammatory cytokine IL-10 by both Foxp3 þ and Foxp3 À T cells, as well as inhibitory ligand receptor interactions (Belkaid, 2007; Curotto de Lafaille and Lafaille, 2009; Langier et al., 2010; Rowe et al., 2012). Treg influence the immune response during a variety of acute viral infections (Rouse et al., 2006; Rowe et al., 2012; Zelinskyy et al., 2009) and are implicated in facilitating persistent infections in both humans and mice (Dittmer et al., 2004; Rowe et al., 2012; Xu et al., 2006). However, their suppressive role and the mechanism(s) of suppression vary depending upon both the pathogen and primary tissue infected. "
    [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.
    Full-text · Article · Dec 2013 · Virology
  • Source
    • "Although CD8+ T-cell functions were augmented after Treg depletion (data not shown), this did not result in faster tumor rejection, most likely because the antitumor CTL were very efficient even under the suppressing influence of Tregs. In contrast, in FV infection, the functional suppression by Tregs mainly targeted CD8+ T cells [40], resulting in the development of functional exhausted CD8+ T cells and in high FV loads in lymphatic organs [16]. Earlier Iwashiro et al. [11] demonstrated that mice persistently infected with FV have approximately twice the normal percentage of splenic CD4+CD25+ Tregs and lose their ability to reject the implantation of FBL-3 cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The important role of tumor-specific cytotoxic CD8+ T cells is well defined in the immune control of the tumors, but the role of effector CD4+ T cells is poorly understood. In the current research, we have used a murine retrovirus-induced tumor cell line of C57BL/6 mouse origin, namely FBL-3 cells, as a model to study basic mechanisms of immunological control and escape during tumor formation. This study shows that tumor-specific CD4+ T cells are able to protect against virus-induced tumor cells. We show here that there is an expansion of tumor-specific CD4+ T cells producing cytokines and cytotoxic molecule granzyme B (GzmB) in the early phase of tumor growth. Importantly, we demonstrate that in vivo depletion of regulatory T cells (Tregs) and CD8+ T cells in FBL-3-bearing DEREG transgenic mice augments IL-2 and GzmB production by CD4+ T cells and increases FV-specific CD4+ T-cell effector and cytotoxic responses leading to the complete tumor regression. Therefore, the capacity to reject tumor acquired by tumor-reactive CD4+ T cells largely depends on the direct suppressive activity of Tregs. We suggest that a cytotoxic CD4+ T-cell immune response may be induced to enhance resistance against oncovirus-associated tumors. Electronic supplementary material The online version of this article (doi:10.1007/s00262-012-1329-y) contains supplementary material, which is available to authorized users.
    Full-text · Article · Aug 2012 · Cancer Immunology and Immunotherapy
Show more