Balancing act

Many microbial infections, such as tuberculosis and malaria, are never eliminated completely by our immune system, even though we can be immune to a second attack. Now, a study in Nature shows that regulatory T (T_Reg) cells at the site of chronic infection might be crucial for parasite persistence and long-lasting immunity.

Infection of C57BL/6 mice with Leishmania major results in a skin lesion that heals after 8–10 weeks, leaving the mouse with long-lasting immunity to the parasite. But, a small number of viable parasites persist. Belkaid and colleagues found that a large number of CD4⁺ T cells are present at the chronically infected site, of which 40–50% are CD25⁺.

The lesion-derived CD4⁺CD25⁺ T cells did not respond to mitogenic stimuli in vitro and, similar to the naturally occurring CD4⁺CD25⁺ T_Reg cells that have been described in autoimmune settings, they could suppress proliferation and the secretion of effector cytokines (such as interferon-γ, IFN-γ) by CD4⁺CD25⁻ effector T cells.

When stimulated with L. major-infected dendritic cells (DCs) in vitro, CD4⁺CD25⁺ T cells from the chronic lesion produced large amounts of interleukin-10 (IL-10), but little IFN-γ or T helper 2 (T_H2) cytokines, such as IL-4 or IL-5. This seems to be an antigen-specific response, as DCs that were infected with other parasites or activated with CD40 failed to induce the secretion of IL-10.

To test the function of these putative T_Reg cells in vivo, lesion-derived T-cell subsets were transferred into lymphopaenic (Rag^−/−) mice, which were then infected with L. major. Mice that received CD4⁺CD25⁻ T cells were highly resistant to infection, whereas those that received CD4⁺CD25⁺ T cells developed severe disease. Mice that received a 1 to 10 ratio of CD25⁺ to CD25⁻ T cells developed a healing lesion with persistent parasites, similar to the response of wild-type mice. This shows clearly that CD4⁺CD25⁺ lesion-derived T cells can suppress L. major immunity. Additional adoptive-transfer experiments indicated that these regulatory cells originate from the naturally occurring CD4⁺CD25⁺ regulatory T-cell pool.

This study shows that a fine balance between regulatory and effector T cells might be essential for parasite persistence. But, it seems that this phenomenon is not just of benefit to the parasite. IL-10-deficient mice clear infection completely, but, unlike wild-type mice, they do not have long-lived immunity. So, by allowing the persistence of parasites, IL-10-secreting T_Reg cells might benefit the host by maintaining protective immunity.