T cell misfits may spell autoimmunity

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For a would-be T cell, the journey from cradle to grave is likely to be brief. After leaving the bone marrow, the immature immune cell travels directly to the thymus, where it undergoes a winnowing process. To become a mature T cell, it must learn to attack alien proteins and not those peptides produced by the body. Precursors that fail this task — because they have a strong affinity for self-peptides — are eliminated. But occasionally an autoreactive T cell will slip by and travel to the periphery, where it can cause disease. In multiple sclerosis, for example, T cells leave the thymus, travel to the brain, and attack a protein in the myelin sheath surrounding nerve fibers. Researchers have wondered how the rogue T cells are able to avoid elimination. It now appears that autoreactive T cells can disguise their presence by altering the way their receptors interact with their target. Kai Wucherpfennig, a Harvard Medical School associate professor of neurology at the Dana Farber Cancer Institute, and colleagues revealed the trick by capturing and crystallizing a T cell receptor. Taken from a patient with multiple sclerosis, the receptor was caught in the act of binding. This is the first time a human autoreactive T cell receptor has been crystallized and imaged. The findings appear in the April 10, 2005, Nature Immunology.