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.

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    • "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. "
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    • "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. "
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    • "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. "
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