For T cell receptors, more activation motifs means less autoimmunity, say Jeff Holst, Dario Vignali (St. Jude's Children's Research Hospital, Memphis, TN), and colleagues.

The T cell receptor's four CD3 subunits contain a total of 10 tyrosine-based activation motifs (ITAMs). These motifs dock with tyrosine kinases inside the cell to promote signaling, but it's unclear why the receptor needs so many ITAMs.

The authors generated mice that expressed mutant CD3 subunits with different numbers of ITAMs. Mice with seven or more ITAMs on their CD3 subunits developed normally, but with six or fewer, mice were prone to autoimmune disease. “Number was more important than ‘flavor,’” Vignali says. Although flavor—the specific ITAM type—also played some part, since two of the four strains with six ITAMs remained healthy.

Autoimmunity can be caused by loss of tolerance for self-antigens during development in the thymus. To test whether ITAM number affected self-antigen recognition, the authors created male mice in which either wild-type or mutant CD3 subunits were combined with a T cell receptor specific for a male antigen. Although wild-type mice deleted thymic T cells bearing the receptor, those with few functional ITAMs allowed the T cells to develop and enter the periphery, where they could provoke an autoimmune reaction. “Self-antigens have to be recognized in the thymus even when affinity and density is low,” Vignali says. The large number of ITAMs might therefore ensure the message isn't lost.

Holst, J., et al.
Nat. Immunol.