Regulatory T Cell Suppressive Potency Dictates the Balance between Bacterial Proliferation and Clearance during Persistent Salmonella Infection

Open Access
Publisher Website
Google Scholar
Abstract
The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3–4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3GFP reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3+ Treg suppressive potency. In complementary experiments using Foxp3DTR mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection. The balance between immune activation and suppression is intricately controlled allowing optimal host defense against infection, while simultaneously minimizing collateral immune-mediated damage to host tissues. Although regulatory T cells have been implicated to play critical roles in sustaining this balance, their role in controlling the dynamic changes in immune cell activation during the natural progression of persistent infection are undefined. Herein, we explored the relative importance of regulatory T cells in controlling infection tempo using a model of persistent Salmonella infection representative of human typhoid. Early after infection when the bacterial burden is progressively increasing, the activation of protective immune components is delayed, and this coincides with increased regulatory T cell suppressive potency. Conversely, later during infection when reductions in bacterial burden occur, protective immune components are highly activated and regulatory T cell suppressive potency is markedly diminished. Moreover, the tempo of persistent Salmonella infection is controlled by regulatory T cells because ablation of these cells early after infection when their suppressive potency is increased accelerates bacterial eradication, while their ablation later when their suppressive potency is reduced causes no significant effects. Thus, regulatory T cell suppression controls the tempo of persistent Salmonella infection.