Role of Foxp3-positive regulatory T cells during infection

Abstract

Surviving an infection requires the generation of an immune response that controls the invading pathogen while limiting collateral damage to self tissues that may result from an exuberant immune response. Various populations of regulatory cells, including Foxp3+ Treg, have been shown to play a central role in the establishment of these controlled immune responses. In this review, I discuss current hypotheses and points of polemic associated with the origin, mode of action and antigen specificity of Foxp3+ Treg during infection.

Figure 1

Foxp3⁺ Treg accumulate at sites of Leishmania infection. TCR^−/− mice were injected with CD4⁺CD25⁻ T cells from cyan fluorescent protein-expressing transgenic mice and CD4⁺Foxp3⁺ Treg from Foxp3-GFP-knock-in mice. Leishmania expressing red fluorescent protein were injected intra-dermally into the ear. This image was taken at 1 month post-infection (red: Leishmania; cyan: CD4⁺CD25⁻ T cells; green: CD4⁺Foxp3⁺ Treg). dysregulation of Treg function requires further analysis.

Figure 2

Origins and specificities of Treg during infections. The origin and antigen specificity of Treg may vary according to the site and the nature of the infection. In acute infection, tissue damage may be associated with enhanced presentation of self antigens. In this case, self-reactive natural Treg may be activated and could, in a bystander manner, limit effector responses against the pathogen. At sites of infection various populations of microbe-specific Treg can be induced (e.g. converted Foxp3⁺ Treg (cFoxp3⁺), Th1 cells producing IL-10 or inducible T reg (Tr1 cells)). In some chronic infections, there is evidence that natural Treg may also accumulate at sites of infection and can recognize microbial antigens. In an environment that is rich in TGF-β and the vitamin A metabolite retinoic acid (RA), such as the gut, peripheral conversion of Foxp3⁻ T cells into Foxp3⁺ Treg may occur in response to food or gut flora antigen or during oral infection. These converted Foxp3⁺ T cells could potentially limit immune responses. Some of these converted cells may be able to recirculate and could contribute to the control of peripheral homeostasis. Red arrows indicate control of immune responses.