During chronic infection, immune systems' T cells often lose their ability to fight pathogens. Research now shows that this T-cell exhaustion is caused by complex negative-feedback pathways that depend on the types of inhibitory receptor the cells express on their surfaces.
By examining gene expression in mice with a chronic infection, John Wherry of the Wistar Institute in Philadelphia, Pennsylvania, and his colleagues found that up to seven inhibitory receptors, which are not made in fully functional T cells, are expressed in exhausted T cells. The more severe the infection, the more members and amounts of this septet the T cells produced.
Simultaneously blocking the function of two such receptors — PD-1 and LAG-3 — incompletely restored exhausted T cells' activity, indicating that multiple pathways are involved in T-cell exhaustion.