Nature Journal Club

Jagadeesh Bayry


An immunologist applauds a protein that prunes intolerant white blood cells.

Spreading tolerance is a worthy cause. In the body, newly made white blood cells are rendered tolerant to the many thousands of native proteins. But, like any complex process, this one is not foolproof, and when it goes wrong intolerant white cells cause autoimmune disease.

One way that the tolerancespreading system can fail is by not having enough ‘field agents’ to pick off intolerant dissenters. Regulatory T lymphocytes (Treg), a type of white blood cell, are these field agents. They find and suppress other white cells that react to healthy parts of the body. Although it is known that people with low Treg levels tend to have autoimmune diseases, how the cells function has been unclear. Recently, however, researchers in Japan shed light on this mystery.

Kajsa Wing, now at the Karolinska Institute in Stockholm, and her colleagues focused on the protein CTLA-4, which is preferentially expressed by Treg cells and forms part of a rheumatoid arthritis drug called Abatacept. They bred mice without CTLA-4 on the surface of their Treg cells. The animals appeared healthy until maturity, then quickly developed autoimmunity. So CTLA-4 is needed for the field-agent system to operate, and merely expressing it in smaller quantities on other sorts of white blood cell isn’t enough. Wing et al. then discovered that CTLA-4 on Treg cells interacts with and diminishes two proteins, CD80 and CD86, on the surface of dentritic cells, which show other white cells what to hunt (K. Wing et al. Science 322, 271–275; 2008).

All of this confirms that CTLA-4 should provide a means of treating autoimmune diseases. Blocking CTLA-4 should improve the capacity of dendritic cells to present dangerous native cells to the immune system. Clinical trials for cancer treatments that do just that are already under way. Now we have a clearer idea how they work.


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