Selective inhibition of immune responses

A discriminating inhibitor for Zap70, a molecule important to propagate activation signals upon antigen recognition by immune T cells, reveals new insights about immune cell signaling and regulation according to a report in this week’s online edition of Nature Immunology. This work points to a new target for immune cell intervention that might prove beneficial in settings where immune tolerance is desired, such as T cell-mediated autoimmunity or organ transplantation.

Zap70 is known to activate a pathway that triggers proliferation and function of effector T cells. Loss of Zap70 function leads to defective T cell development, hence how Zap70 functions in mature T cells was left unknown.

Art Weiss and colleagues generated small molecule inhibitors targeting a modified version of Zap70. They show an unexpected new function of Zap70 in regulatory T cells, which act to prevent autoimmune responses and restrains effector T cells. While the new inhibitors block the catalytic activity of modified Zap70 kinases and thereby blocked effector cell functions, which are important for combating infections, the suppressive activity of regulatory T cells remains intact. These findings point to a kinase-independent role for Zap70 in regulatory T cells.