Regulatory T cells: friend or foe in immunity to infection?

Abstract

There are distinct populations of natural and inducible regulatory T cells that have the common property of suppressing immune responses. Natural regulatory T cells arise in the thymus and express CD25 and the transcriptional repressor FOXP3 (forkhead box P3), whereas inducible regulatory T cells are generated from naive T cells in the periphery after encounter with antigen. Regulatory T cells suppress the proliferation of and cytokine production by T helper 1 (T_H1) cells, T_H2 cells and CD8⁺ T cells, either by cell–cell contact mechanisms or through production of the immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-β. Infection with many (and perhaps all) pathogens that cause persistent or chronic infections is associated with the induction of regulatory T cells specific for pathogen-derived antigens. The induction of regulatory T cells specific for pathogen-derived antigens is directed by semi-mature dendritic cells, which have an intermediate phenotype that includes low-level expression of CD40 and production of IL-12 but high levels of IL-10 production. Immune responses that help to eliminate pathogens can cause collateral damage to host tissues, and if they are not tightly regulated, they can exacerbate the course of disease through the development of immunopathology. Regulatory T cells have a protective role in infection by limiting pathogen-induced immunopathology, while allowing the development of immunological memory. Most pathogens have evolved sophisticated mechanisms of survival through the evasion and subversion of host immune responses. Regulatory T cells can be exploited by pathogens to subvert the protective immune responses of the host, thereby enabling pathogen persistence and the development of a state of chronic infection. Suppression of the activation of regulatory T cells or their cytokine production is a promising approach for the development of therapies for chronic infections, as well as cancer, but it has the risk of promoting inflammation and autoimmunity.