Immune privilege in sites of chronic infection: Leishmania and regulatory T cells

Abstract

Leishmania are digenetic protozoan parasites that are inoculated into the skin by vector sand flies, are taken up by macrophages, and produce a spectrum of chronic diseases in their natural reservoir and susceptible human hosts. During the early establishment of infection in the skin and lymphoid organs, Leishmania produce multiple effects on macrophage and dendritic cell functions that inhibit their innate anti-microbial defenses and impair their capacity to initiate T-helper 1 cell immunity. In addition, the skin is a site preconditioned for early parasite survival by virtue of a high frequency of steady-state, natural CD25+Foxp3+ regulatory T cells (Tregs) that function to suppress the generation of unneeded immune responses to infectious and non-infectious antigens to which the skin is regularly exposed. In murine models of infection, antigen-induced CD25+/-Foxp3-interleukin (IL)-10+ Treg cells act during the effector phase of the immune response to control immunopathology and may also delay or prevent healing. Finally, following resolution of infection in healed mice, CD25+Foxp3+ Tregs function in an IL-10-dependent manner to prevent sterile cure and establish a long-term state of functional immune privilege in the skin.