Abstract

The coreceptor cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is pivotal in regulating the threshold of signals during T cell activation, although the underlying mechanism is still not fully understood. Using in vitro migration assays and in vivo two-photon laser scanning microscopy, we showed that CTLA -4 increases T cell motility and overrides the T cell receptor (TCR)-induced stop signal required for stable conjugate formation between T cells and antigen-presenting cells. This event led to reduced contact periods between T cells and antigen-presenting cells that in turn decreased cytokine production and proliferation. In addition, CTLA -4 ligation prevented TcR complex induction of ZAP -70 microclusters needed for the tyrosine phosphorylation cascade in T-cells. These results suggest a fundamentally different model of reverse stop signaling, by which CTLA -4 modulates the threshold for T cell activation and protects against autoimmunity.