Immune regulation

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 (TReg) 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+ TReg 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 (TH2) 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 TReg 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 TReg cells might benefit the host by maintaining protective immunity.

References

ORIGINAL RESEARCH PAPER

  1. 1

    Belkaid, Y. et al. CD4+ CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002)

FURTHER READING

  1. 2

    Shevach, E. M. CD4+CD25+ suppressor T cells: more questions than answers. Nature Rev. Immunol. 2, 389–400 (2002)

  2. 3

    Sacks, D. & Noben-Trauth, N. The immunology of susceptibility and resistance to Leishmania major in mice. Nature Rev. Immunol. 2, 845–858 (2002)

Download references

Authors

Related links

Related links

WEB SITES

Ethan Shevach's lab

David Sacks' lab

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bell, J. Balancing act. Nat Rev Immunol 3, 3 (2003). https://doi.org/10.1038/nri991

Download citation

Further reading