Parasite-specific natural T reg cells (green) are activated in the draining lymph nodes of mice chronically infected with Leishmania major.

Naturally occurring regulatory T (T reg) cells suppress T cell–driven autoimmunity and chronic inflammation. Although the origin and function of these cells has been widely studied, the specificity of their T cell receptors (TCRs)—whether for self or foreign antigens on target cells—remains a matter of debate. Prevailing opinion comes down on the side of self-antigen. But now Suffia and colleagues (page 777) show that a majority of these T reg cells, at least those that congregate at the site of chronic parasite infection in mice, recognize the bug, not the mouse.

In earlier work, the group showed that this kind of T reg cell accumulated in the skin of mice infected with the parasite Leishmania major, thus hampering the response of effector T cells and allowing the bug to settle in for the long haul. They now show that most of these T reg cells are parasite specific, as they divided extensively when exposed to L. major-infected dendritic cells.

Unlike self-reactive T reg cells, which are thought to circulate throughout the body, these parasite-specific T reg cells stayed put, inhabiting the infected skin and nearby draining lymph node, but not venturing to distant sites. This localization probably reflects a dependence on antigen for survival, as the T reg cells rapidly died off when the infection was eliminated. The strict corralling of the antigen-specific T reg cells makes sense, says senior author Yasmine Belkaid, as escape of these cells could cause systemic immunosuppression.

These data do not suggest that self-reactive T reg cells don't exist, but rather prove that antigen-specific ones do. Belkaid suspects that localized bug-specific T reg cells are a common feature of chronic infections with pathogens that have coevolved with the host. These parasites might have become adept at activating T reg cells as a way to help ensure their survival.