On the other hand, allowing pathogen persistence by dampening immune activation may also be beneficial when immune-mediated collateral damage to the host outweighs injury caused by pathogen persistence. In this regard, Treg cells play important roles in counterbalancing immune effectors during persistent infection. This was first described 10 years ago for Leishmania major infection, where immune suppression
by CD25+ CD4+ Treg cells was found to promote pathogen persistence in the skin after intra-dermal infection.11 More recently, these findings have been recapitulated for other persistent infections using more refined strategies that allow Treg-cell manipulation based on Foxp3 expression. For example, the ablation of Foxp3+ cells based on selective expression of the Thy1.1 MAPK Inhibitor Library molecular weight congenic marker in mixed bone marrow chimera mice before pulmonary infection with Mycobacterium tuberculosis stimulates more robust effector CD4+ T-cell interferon-γ production and reduced pathogen burden at the site of infection.58 Similarly, Foxp3+ Treg cells provide a similar protective role in a model
of typhoid fever caused by persistent Salmonella Sirolimus order infection in Nramp1-resistant mice.59 At early time-points following infection when the activation of effector T cells is blunted and progressively increasing Salmonella bacterial burden occurs, Treg-cell ablation in Foxp3DTR mice accelerates
the activation of effector T cells with significant reductions in recoverable bacteria.59 In turn, at later time-points during persistent Salmonella infection when effector T cells are already activated and progressive reductions in pathogen burden naturally occur, the impacts of Foxp3+ cell ablation are marginalized with only modest incremental augmentation of effector T-cell activation and no significant changes in pathogen burden.59 Hence, Foxp3+ Treg cells blunt effector T-cell activation that impedes pathogen eradication, and the significance of Treg-cell-mediated immune suppression can shift and dictate the tempo of some persistent Cepharanthine infections. Although these results suggest that Treg cells play detrimental roles in host defence by preventing pathogen eradication, the reduced susceptibility against secondary infection related to low-level pathogen persistence for other pathogens (e.g. Leishmania and Plasmodium) illustrates that Treg cells may in fact provide protection against more severe disseminated infection with potentially fatal consequences.30,60,61 It will be interesting to investigate if these Treg-cell-mediated protective activities against secondary infection are more broadly applicable for other pathogens that cause persistent infection.